60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis

in Journal of Endocrinology

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.

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.

Introduction

When Geoffrey Harris wrote his influential monograph on ‘Neural Control of the Pituitary Gland’, it was already apparent that prolactin, or ‘lactogenic hormone’ as he referred to it, might be controlled differently to the other adenohypophyseal hormones. Harris convincingly built the case that humeral factors from the hypothalamus control secretion of anterior pituitary hormones, correctly predicting the existence of hypothalamic ‘releasing factors’ that mediate the neural control of pituitary secretions (Harris 1948). Despite the clear evidence that neural stimuli (such as suckling) could stimulate prolactin secretion, however, Harris noted that cutting the pituitary stalk did not abolish lactation (Dempsey & Uotila 1940), leading to the inevitable conclusion that a hypothalamic ‘prolactin-releasing factor’ was not necessary to stimulate prolactin secretion. Indeed, it was subsequently shown in hypophysectomised rats that ectopic pituitary grafts were able to maintain corpus luteum function (Everett 1954) and lactation (Cowie et al. 1960), demonstrating hypothalamic-independent secretion of prolactin from the grafts. At first impression, this appeared to contradict Harris' principle of neural control of the anterior pituitary. But further observations identified the fact that hypothalamic regulation was indeed critical for normal prolactin secretion, as Harris predicted, but that the mode of control was different. Everett found that while pituitaries located away from the hypothalamus would induce pseudopregnancy, a marker of elevated prolactin secretion in rodents, normal cycles (and therefore normal low levels of prolactin) would resume if transplanted pituitaries were re-vascularised by portal vessels under the median eminence (Nikitovitch-Winer & Everett 1958). Two groups independently demonstrated that extracts of the median eminence/infundibular region could inhibit prolactin secretion from anterior pituitary cells in vitro (Pasteels 1963, Talwalker et al. 1963). Subsequently, it was shown that median eminence lesions (Arimura et al. 1972) or destruction of the pituitary stalk (Kanematsu & Sawyer 1973) resulted in elevated prolactin secretion (accounting for the pseudopregnancies described earlier by Everett). Thus, it was proven that the hypothalamus was essential for the regulation of prolactin secretion, but that it primarily exerted an inhibitory influence.

This brief review will summarise our current understanding of the hypothalamic control of prolactin secretion, and the neuroendocrine functions of prolactin, highlighting (admittedly selected) areas of current research interest. From the somewhat contrary beginnings previously introduced, the neural control of prolactin secretion, and indeed the whole hypothalamo-prolactin axis, continues to prove itself a bit different from other hypothalamo-pituitary systems. Not only is the hypothalamic regulation predominantly inhibitory, as opposed to stimulatory, it also involves a catecholamine neurotransmitter, dopamine, rather than the more typical peptide hypothalamic hormones involved in regulating all other pituitary systems. Prolactin is also the only anterior pituitary hormone that does not have an endocrine target tissue, and therefore lacks a classical hormonal feedback system. It is regulated, instead, by a short loop feedback whereby prolactin itself stimulates the secretion of the inhibitory factor, dopamine. Finally, despite its rather simple and one-dimensional name, prolactin does much more than simply PROmote LACTation. It is now recognised as a pleiotrophic hormone with arguably the widest range of physiological actions of any extracellular signalling molecule in the body.

Neuroendocrine control of prolactin secretion

Dopamine as a prolactin-inhibitory hormone

Even after the clear demonstration of inhibitory regulation of prolactin secretion in the 1950s, the search for the inhibitory hormone mediating this action was controversial. All hypothalamic hormones identified to date had been peptides, and the expectation was that ‘prolactin-inhibitory factor’ would also be a peptide. Initial clues that this might not be the case came from observations that drugs such as reserpine, which depletes endogenous catecholamines, induced pseudopregnancy in rats (Barraclough & Sawyer 1959), indicative of elevated prolactin. It was assumed, however, that the functional role of catecholamines were as neurotransmitters acting in the hypothalamus to regulate the release of a hypothalamic hormone (Kanematsu et al. 1963). Based on the evidence of dopaminergic nerve terminals in the median eminence (Fuxe 1963), McLeod proposed that dopamine may be released into the pituitary portal system, and thereby acting as a hypothalamic hormone (as distinct from its neurotransmitter role in other systems) (MacLeod et al. 1970). He demonstrated that dopaminergic agonists were effective at suppressing prolactin secretion in vivo, and perhaps more importantly, that dopamine could inhibit prolactin secretion from isolated pituitary glands (MacLeod et al. 1970). Dopamine was subsequently detected in the pituitary portal blood (Kamberi et al. 1970), and Porter's group (and others) found that variations of levels of dopamine in the portal blood accounted for changes in prolactin secretion in various physiological conditions (Ben-Jonathan et al. 1977, 1980, Gibbs & Neill 1978, De Greef & Neill 1979). Dopamine receptors were identified on lactotroph cells in the anterior pituitary (Mansour et al. 1990). The observation that mice lacking the dopamine D2 receptor are hyperprolactinemic (Kelly et al. 1997, Saiardi et al. 1997), clearly demonstrated the critical role of dopamine in suppressing endogenous prolactin secretion (see Fig. 1).

Figure 1
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.

Citation: Journal of Endocrinology 226, 2; 10.1530/JOE-15-0213

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.

Electrophysiological studies of hypothalamic dopamine neurons in the rat have described TIDA neurons as exhibiting a robust oscillation between hyperpolarized and depolarized states, with periodicity of about 20 s, and a spontaneous firing rate of ∼4 Hz during the depolarized ‘up-state’. Remarkably, the TIDA neurons were found to show a synchronous pattern of firing suggestive of an interconnected network, dependent on functional expression of gap junctions (Lyons et al. 2010). Taking advantage of transgenic technologies to label dopaminergic neurons with fluorescent tags, studies of TIDA electrical activity have also been completed in brain slices from mice (Brown et al. 2012, Romano et al. 2013), showing a similar pattern of firing to that seen in the rat, although only a small proportion of TIDA neurons showed the phasic oscillations in this model. Importantly, one of these latter studies demonstrated that patterns of firing of an individual TIDA neuron were reflected in the pattern of dopamine release from the population, as measured using in vivo amperometry in the median eminence (Romano et al. 2013). These data support the concept postulated by Lyons et al. (2010), that the neurons act as a synchronous network to release dopamine in a pulsatile or phasic fashion.

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).

Prolactin regulation of dopamine neurons: short loop feedback

As previously mentioned, the hypothalamo-prolactin system does not have a specific endocrine target, and therefore lacks the classical hormone-mediate negative feedback pathway described for all other anterior pituitary hormones. Nevertheless, it is still regulated in a negative feedback manner, with prolactin itself providing the afferent signal in a process known as short-loop feedback. The presence of prolactin receptors on dopamine neurons (Lerant & Freeman 1998, Grattan 2001, Kokay & Grattan 2005) was predicted by early neurochemical studies that showed that exogenous prolactin stimulated hypothalamic dopamine synthesis (Hokfelt & Fuxe 1972) and turnover (Eikenburg et al. 1977, Annunziato & Moore 1978), increased dopamine metabolism in the median eminence (Lookingland et al. 1987) and promoted dopamine secretion into the pituitary portal blood (Gudelsky & Porter 1979). In contrast, hypoprolactinemia induced by administration of dopamine agonists resulted in suppression of dopamine secretion (Arbogast & Voogt 1991a), indicating that the basal activity of these neurons is dependent on the endogenous levels of prolactin present in the blood. Using these biochemical indices of activity of TIDA neurons, the time course of prolactin action was described as having a ‘rapid’ component of increased activity observed 2–4 h after prolactin treatment (Selmanoff 1985), and a delayed component seen ∼12 h after prolactin treatment (Demarest et al. 1984a, 1986). More recent electrophysiological data has demonstrated even more rapid actions of prolactin on the electrical activity of TIDA neurons in mice (Brown et al. 2012, Romano et al. 2013) or rats (Lyons et al. 2012). These studies show that prolactin induces a fourfold increase in firing rate within seconds to minutes of application, acutely changing the firing pattern from a basal phasic pattern to a tonically active pattern. Hence, there seem to be multiple mechanisms of prolactin regulation of these dopamine neurons mediated over different time courses.

It was observed that prolactin feedback was markedly impaired in mice lacking the transcription factor STAT5b (Grattan et al. 2001), likely through impairment in the long-term regulation of expression of the rate limiting enzyme in dopamine synthesis, tyrosine hydroxylase (Arbogast & Voogt 1991a, Ma et al. 2005). While such an effect might account for the ‘delayed’ component of prolactin feedback, which requires protein synthesis (Johnston et al. 1980), it is unlikely to account for more rapid components of short look feedback. The very rapid action revealed by electrophysiology appears to involve two components: a low voltage component from transient receptor potential (TRP)-like current and high voltage component from inhibition of a Ca2+-dependent BK-type K+ current, with the latter component being wortmannin sensitive, suggesting an involvement of the PI3K pathway (Lyons et al. 2012). The slower component, originally described as ‘rapid’ in neurochemical experiments, with a time course of minutes to hours, likely involves prolactin-induced serine phosphorylation of tyrosine hydroxylase (Ma et al. 2005), resulting in increased enzyme activity (Arbogast & Voogt 1997). Together, these three layers of prolactin regulation of hypothalamic dopamine neurons provides a tight homeostatic control, with prolactin rapidly increasing the firing rate of these neurons to induce increased dopamine secretion into the portal blood and rapid suppression of further prolactin secretion from the lactotroph. At the same time, slower but more prolonged changes in tyrosine hydroxylase phosphorylation and transcriptional events to maintain changes in tyrosine hydroxylase gene transcription serve to regulate neuronal function over a much longer time-course, priming the neurons for continued responses to changes in prolactin levels (Grattan & LeTissier 2015).

For endogenous prolactin to function in the short-loop feedback manner, previously described, one important consideration is how this relatively large (197–199 amino acids; 21 kDa) polypeptide hormone crosses the blood brain barrier to gain access to the dopamine neurons. While it is possible that the arcuate nucleus/median eminence region may have an incomplete blood-brain barrier such that hormones can directly access to neurons in this area (Schaeffer et al. 2013), it seems unlikely that this is the major mechanism by which prolactin regulates the hypothalamic dopamine neurons. Indeed, systemic administration of prolactin has been shown to simultaneously activate neurons throughout the hypothalamus (Brown et al. 2010, Sapsford et al. 2012), not simply in the arcuate nucleus. There is clear evidence that systemic prolactin crosses the blood brain barrier through a saturable, carrier-mediated transport system (Walsh et al. 1987). As a result, prolactin levels in the cerebrospinal fluid parallel changes in prolactin in the peripheral circulation (Login & MacLeod 1977, Nicholson et al. 1980, Grattan & Averill 1991). Because of the high levels of prolactin receptor expression and prolactin binding seen in the choroid plexus (Walsh et al. 1978, 1990, Pi & Grattan 1998a,b, Augustine et al. 2003), it has been widely assumed that the prolactin receptor might mediate prolactin entry into the cerebrospinal fluid. However, we have recently shown that prolactin transport into the brain is independent of the prolactin receptor, occurring just as well in prolactin receptor knockout mice (Brown RSE, Wyatt AK, Herbison RE, Knowles PJ, Ladyman SR, Binart N, Banks WA & Grattan DR, unpublished observations). Hence, precise mechanism that translocates prolactin from the blood into the CSF remains to be determined.

Plasticity in prolactin feedback during lactation

In order to support a period of hyperprolactinemia during lactation, and thereby promote the milk production that is essential to this state, there is an apparent loss of sensitivity of the short-loop feedback system during late pregnancy and lactation (Grattan et al. 2008). This is a remarkable example of adaptive plasticity within a neuroendocrine control network, allowing a sustained period of high prolactin secretion to be maintained unencumbered by a regulatory feedback pathway (see Fig. 2). The mechanisms mediating this adaptive response are only recently becoming elucidated. Up until late pregnancy in rodents, normal negative feedback regulation of prolactin secretion dominates, as previously described, but high levels of placental lactogens are produced. As placental lactogen binds to and activates prolactin receptors, this mimics prolactin action and bypasses the feedback inhibition to ensure that prolactin responsive functions are highly stimulated at this time. Activity of hypothalamic dopamine neurons is maintained by the presence of placental lactogen, so pituitary prolactin secretion is low. Despite the continued presence of placental lactogens, however, there is a decrease in activity of the dopamine neurons during late pregnancy (Andrews et al. 2001) associated with a nocturnal surge in pituitary prolactin secretion immediately before parturition (Grattan & Averill 1990, 1995). Hypothalamic dopamine neurons apparently no longer release dopamine in response to prolactin or placental lactogen at this time, rendering the short-loop negative feedback system functionally inactive (Grattan & Averill 1995, Fliestra & Voogt 1997). This adaptation persists into lactation, and dopamine secretion remains low throughout this period of elevated prolactin secretion (Ben-Jonathan et al. 1980, Demarest et al. 1983). This is an important adaptation, because prolactin is required for milk production and maternal behaviour at this time.

Figure 2
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.

Citation: Journal of Endocrinology 226, 2; 10.1530/JOE-15-0213

There is a highly coordinated release of prolactin during lactation, caused by the suckling stimulus. This is associated with a decrease in dopamine turnover in hypothalamic dopamine neurons (Selmanoff & Wise 1981, Demarest et al. 1983, Selmanoff & Gregerson 1985) and a profound suppression of tyrosine hydroxylase mRNA levels (Wang et al. 1993). The original perception that hypothalamic dopamine neurons show a ‘loss of response’ to prolactin at this time has proved to be incorrect. In fact, prolactin receptor expression in the dopamine neurons is maintained (Kokay & Grattan 2005), and acute electrophysiological responses to prolactin persist in lactation (Romano et al. 2013). Downstream of the prolactin receptor, however, there is a change in the cellular response. Serine 40 phosphorylation of tyrosine hydroxylase in the median eminence is decreased (Feher et al. 2010, Romano et al. 2013), resulting in a reduction in the activity of this enzyme (and a reduction in dopamine synthesis). Strikingly, there is a disconnection between neuronal firing and dopamine release at the median eminence. Even though the electrophysiological response to prolactin is unchanged, there is no longer detectable release of dopamine in the median eminence (Romano et al. 2013). Prolactin-induced activation of STAT5b in dopamine neurons is reduced during lactation, potentially mediated by an up-regulation of endogenous inhibitors of STAT signaling, the suppressors of cytokine signaling (SOCS) proteins (Anderson et al. 2006a,b, Steyn et al. 2008). At the same time as the loss of dopamine secretion, there is an increase in met-enkephalin expression in the dopamine neurons (Merchenthaler 1993, 1994, Szabo et al. 2011), and it seems possible that elevated prolactin may drive this met-enkephalin expression (Nahi & Arbogast 2003). Hence, the neurons essentially change their phenotype, changing from being dopaminergic to enkephalinergic. As they still respond electrophysiologically to prolactin, they may be mediating a completely different function of prolactin in the brain during lactation.

It is interesting to note that while the suckling-induced prolactin secretion could be consistent with the ‘dopamine withdrawal’ or ‘disinhibition’ model of prolactin secretion, previously discussed, the chronic reduction in dopamine output seen during lactation complicates this interpretation. If dopamine production is lost, as implied in the data of Romano et al. (2013), how can suckling cause an acute increase in prolactin secretion through dopamine withdrawal? Perhaps this is evidence that a suckling-induced ‘prolactin-releasing factor’ may be involved in stimulating prolactin secretion at this time (see further discussion of prolactin-releasing factors in the following section). It is well established that enkephalin can promote prolactin secretion (Cusan et al. 1977), and while most evidence suggests that this effect is mediated centrally through regulation of TIDA neurons, it can also act in the pituitary gland to antagonize dopaminergic inhibition of lactotrophs (Enjalbert et al. 1979). Could the lactation-specific release of enkephalin from TIDA neurons be functioning as a prolactin-releasing factor, either in the classical sense, by regulating lactotroph function via the portal blood, or through a more local effect on TIDA neurons within the median eminence? Either way, the idea that prolactin might be promoting its own secretion through the same neurons that normally inhibits its secretion, essentially switching from negative to positive feedback at a time when high levels of prolactin are required, is a provocative one worthy of further investigation.

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.

Role of a ‘prolactin-releasing factor’?

Ever since Harris' first proposal of the humeral control of the anterior pituitary gland, researchers have searched for a ‘prolactin-releasing factor’ to match that of other pituitary hormones. There have been some notable discoveries, but to date, convincing evidence for a physiological prolactin-releasing factor has not been forthcoming (for reviews, see Freeman et al. (2000), Ben-Jonathan & Hnasko (2001) and Crowley (2015)). Most of the factors that regulate prolactin secretion do so by directly or indirectly influencing dopamine secretion from the hypothalamic dopamine neurons. The best example of this is prolactin itself, which stimulates dopamine release to inhibit its own secretion (previously discussed). Other examples are opioid peptides, which are potent stimulators of prolactin secretion, and act predominantly through an inhibition of dopamine neurons. Alternatively, factors may stimulate prolactin secretion through an action on the pituitary gland. The ovarian steroid, estradiol, is an excellent example, acting on lactotrophs to increase prolactin gene expression and increase levels of prolactin released in response to other stimuli (Fink 1988). Neither of these actions would classify as a hypophysiotrophic ‘prolactin releasing factor’, as defined by Harris. For this, the factor would need to be produced in the hypothalamus, be secreted into the portal blood, and act in the pituitary gland to stimulate prolactin secretion (and thereby oppose the actions of the hypothalamic inhibitory hormone).

The levels of prolactin achieved by administration of dopamine antagonists are as high as one would normally associate with prolactin release stimulated under physiological conditions, such as in response to the suckling stimulus (Andrews & Grattan 2004). Thus, it would seem possible to account for most stimulated prolactin secretion simply by a process of disinhibition, removing the normal dopaminergic inhibitory control. However, whether such a total withdrawal of dopamine ever occurs in vivo is unlikely (Martinez de la Escalera & Weiner 1992). There is continued interest in the possibility that a physiological ‘prolactin-releasing factor’ exists. Vasoactive intestinal polypeptide (VIP) may be the ancestral regulator of prolactin secretion, since it is the primary ‘prolactin-releasing factor’ in non-mammalian vertebrates (Horseman 1995), and it has stimulatory effects on prolactin secretion in mammals (Murai et al. 1989). However, while produced in both the hypothalamus and in the pituitary gland, it is unlikely that VIP acts as a hypophysiotrophic releasing factor, in the sense defined by Harris. It does not appear to be secreted into the portal system at levels higher than in the systemic circulation, nor is it present at elevated levels in the blood at all times that prolactin secretion is high. The same is probably true for a large number of factors that have been investigated as putative ‘prolactin releasing hormones’, including thyrotropin-releasing hormone, oxytocin, galanin, salsolinol, prolactin-releasing peptide and others (reviewed in Freeman et al. (2000), Crowley (2015) and Grattan & LeTissier (2015)). Many of these factors may influence prolactin secretion, either from effects on hypothalamic dopamine neurons, or from effects on pituitary lactotrophs, but none have proven to meet the criteria to be considered hypothalamic hypophysiotrophic factors.

Freeman's group tackled this question by investigating whether changes in prolactin could be observed independently of dopaminergic inhibition. They observed that administration of the D2 antagonist domperidone induced different levels of prolactin secretion at different times of the day (Arey et al. 1989). Assuming that antagonism of dopamine was complete at each time point, they interpreted these data to demonstrate the existence of an ‘endogenous stimulatory rhythm’, where factors from the hypothalamus (including oxytocin and VIP) were promoting prolactin secretion at specific times in dependently of dopamine (Arey & Freeman 1990, 1992a,b), but this stimulation was usually masked by the prevailing dopaminergic tone. Importantly, they also showed that endogenous stimuli that reduce dopamine input to the pituitary, such as suckling, could also reveal this stimulatory rhythm, promoting different levels of prolactin secretion at different times of the day (Arey et al. 1991). These data provide convincing evidence of dopamine-independent regulation of prolactin secretion, but cannot conclusively prove it is mediated by a ‘prolactin-releasing factor’. An alternative possibility is that endogenous circadian regulators within the pituitary gland might influence that amount of prolactin released at different times of the day (Becquet et al. 2014). Circadian regulation of prolactin secretion has also been documented via melatonin actions in the pars tuberalis (Lincoln et al. 2003).

If there is a physiological ‘prolactin-releasing factor’, it remains elusive. One possible reason for this is that the stimulatory control exerted from the hypothalamus may not be a ‘classical’ system, as defined by Harris. In the late 1980s and early 1990s, there was a particularly well-developed story regarding a putative prolactin-releasing factor coming from a subpopulation of melanotrophs in the intermediate lobe of the pituitary, as opposed to the median eminence. This factor was originally discovered by Murai & Ben-Jonathan (1987, 1990), who showed that surgical removal of the posterior pituitary (including the intermediate lobe) impaired the prolactin release in response to estradiol administration or suckling. This was subsequently supported by a number of other groups, with studies demonstrating reduced or absent prolactin secretion after removal of the neurointermediate lobe (Samson et al. 1990, Averill et al. 1991, Andrews & Grattan 2004). Moreover, mice with secretory tumours of the intermediate lobe were hyperprolactinemic (Allen et al. 1995). Despite extensive effort at characterisation, particularly from the Ben-Jonathan group, the specific identity of this factor (or factors) has not been identified, although a number of known prolactin secretagogues (TRH, oxytocin, VIP) were excluded (Allen et al. 1995, Hnasko et al. 1997). Nevertheless, this highlights the possibility that ‘non classical’ prolactin releasing systems may remain to be discovered.

Based on the magnitude of prolactin release in response to dopamine inhibition (Andrews & Grattan 2004), I have previously held the view that most prolactin release could be accounted for by a decrease in dopamine. Our new data showing that even after marked reductions in dopamine secretion during lactation in mice (Romano et al. 2013), there is a sustained ability to regulate prolactin secretion in response to suckling, however, has forced a re-think of this view. It would seem that other regulatory factors must be involved in the physiological regulation of prolactin secretion, particularly during lactation when it is most required. Whether one or more of these factors becomes the long sought ‘prolactin-releasing factor’ predicted by Harris remains an exciting area needing further investigation.

Regulation of prolactin secretion by estradiol

The ovarian steroid estradiol is arguably one of the most important regulators of prolactin secretion in several different physiological states. In the pituitary gland, estradiol is a major stimulator of prolactin secretion, although this is principally through a classical genomic regulation of prolactin gene expression (Lieberman et al. 1981), by increasing the number of lactotrophs (Takahashi et al. 1984, Scully et al. 1997, Kansra et al. 2005, 2010, Nolan & Levy 2009) and by modifying lactotroph responsiveness to other regulators (De Lean & Labrie 1977, Raymond et al. 1978, West & Dannies 1980), although a rapid non-genomic actions of estradiol stimulating prolactin secretion have been described (Huerta-Ocampo et al. 2005). The TIDA neurons also express receptors for both estradiol (estrogen receptor alpha (ERα)) and progesterone (Sar 1984, 1988, Fox et al. 1990, Lonstein & Blaustein 2004, Steyn et al. 2007), and gonadal steroids regulate prolactin secretion indirectly through actions on these neurons (Jones & Naftolin 1990, Arbogast & Voogt 1993, 1994, DeMaria et al. 2000). These actions of estradiol are particularly important during the reproductive cycle and during pregnancy. The predominant direct action of estradiol on TIDA neurons is one of inhibition (Demarest et al. 1984b, Arita & Kimura 1987, DeMaria et al. 2000, Morel et al. 2009), suppressing TH expression (Blum et al. 1987, Morrell et al. 1989) and activity (Pasqualini et al. 1993), and reducing secretion of dopamine into the portal blood (Cramer et al. 1979), thereby facilitating prolactin secretion. The estradiol-induced proestrous prolactin surge is associated with a steroid-dependent decline in TIDA activity (DeMaria et al. 1998, Yen & Pan 1998, Liu & Arbogast 2008, 2010), with a prominent role for progesterone suppressing dopamine release during the plateau phase of the surge (Arbogast & Ben-Jonathan 1990, Arbogast & Voogt 1994). Similarly, ovarian steroids play a critical role in controlling the twice-daily prolactin surges required to sustain luteal function pregnancy in rodents (Gunnet & Freeman 1983, Arbogast & Voogt 1991b). The rising levels of estradiol during pregnancy are also critical to promoting prolactin secretion, particularly during late pregnancy (Grattan & Averill 1990, Andrews 2005), and to the plasticity in the TIDA neurons as previously described (Grattan et al. 2008). In addition to regulation of prolactin secretion, estradiol may also regulate the cellular responses to prolactin. In the brain, many of the neurons expressing the prolactin receptor also express ERα (Furigo et al. 2014). Estradiol may regulate prolactin receptor expression on neurons (Lerant & Freeman 1998), and several of the actions of prolactin are dependent on the presence of estradiol (Anderson et al. 2008). Thus, estradiol acts at multiple levels to both directly and indirectly regulate prolactin synthesis, secretion and action.

Neuroendocrine functions of prolactin

Prolactin was identified and named for its critical role in the physiology of lactation, and this remains its best-characterised function. Prolactin is indispensible for lactation. However, a vast array of additional functions has also been characterised. These have been thoroughly reviewed by Paul Kelly's group (Bole-Feysot et al. 1998), who classified the functions under six broad headings: water and electrolyte balance, growth and development, endocrinology and metabolism, brain and behaviour, reproduction and immune regulation and protection. The breadth of potential functions is astounding and difficult to conceptualise into a theoretical framework. Many of the reported actions of prolactin appear to be redundant, as evidenced by the lack of a significant phenotype in the prolactin or prolactin-receptor knockout mice. This may simply be the evolutionary result of a phylogenically old signalling molecule being used for multiple adaptive roles in homeostasis. One can see examples where prolactin has subserved similar functions across many species. For example, in fish and amphibia, it is involved in electrolyte balance, and movement of ions and water across epithelial barriers (Bole-Feysot et al. 1998). Perhaps this is not so different from inducing secretion of nutrients and electrolytes from an epithelial gland, as in the crop milk of pigeons, and the breast milk of mammals. Similarly, prolactin has been implicated in parental behaviour ranging from nest fanning in fish, through to incubation and brooding behaviour in birds, to lactation and maternal behaviour in mammals. When viewed from an evolutionary context, it seems logical that the nurturing parental behaviour actions of prolactin might have evolved in parallel with a nutrient synthesis and secretion role, providing an adaptive advantage of novel reproductive strategies.

There is insufficient space in this review to do justice to the wide range of potential prolactin-sensitive functions. Instead, I have taken the strategy of focusing on functions that are specifically regulated when endogenous prolactin levels are high. Apart from the estrogen-induced prolactin surge during the female reproductive cycle (which may not occur in all species (Ben-Jonathan et al. 2008), and the response to stress, which is transient and of low magnitude (Gala 1990), prolactin levels are typically maintained at low levels as a consequence of the highly effective short loop negative feedback. The exception to this is pregnancy and lactation, where mammals exhibit at least three adaptations to ensure high levels of lactogenic hormone activity throughout these conditions (see Fig. 2). First, there is the production of placental lactogen and/or decidual prolactin, lactogens from reproductive tissues. These hormones act on the prolactin receptor, and therefore bypass the short-loop feedback regulation of the anterior pituitary gland to provide constantly elevated levels of lactogenic hormones throughout pregnancy. Secondly, there are the adaptive changes in feedback occurring in the maternal hypothalamic dopamine neurons, previously discussed, changing the manner in which they respond to prolactin, enabling high secretion to prolactin to be maintained from the maternal pituitary after the pregnancy-specific placental lactogens are lost at parturition. Thirdly, there is the hormone-dependent expression of maternal behavior, with the consequent suckling stimulus from the pups providing the most powerful stimulus to pituitary prolactin secretion that is known in mammals. As previously discussed, this might involve chronic and/or acute dopamine withdrawal, as well as the additional stimulus of an as yet unidentified ‘prolactin-releasing factor’ to maintain elevated levels of prolactin. Finally, we have recent evidence suggesting that transport of prolactin into the brain is increased during lactation (Brown RSE, Wyatt AK, Herbison RE, Knowles PJ, Ladyman SR, Binart N, Banks WA & Grattan DR, unpublished observations), suggesting that many of the CNS functions of prolactin might be further enhanced at this time. These multiple adaptive changes make a compelling argument to focus on pregnancy and lactation as the most critical time for prolactin actions in the body.

It is absolutely clear that these elevated levels of lactogenic hormones are required for development of the mammary gland during pregnancy and for milk production during lactation. The regulation of mammary function by prolactin is extensively reviewed elsewhere (Hovey et al. 2001, Trott et al. 2012). It is important to recognize, however, that prolactin and placental lactogen are also able to act in a wide variety of other tissues in the body. The prolactin receptor is widely expressed in numerous body systems, including bone, adipose tissue, gut, reproductive tract, skin, immune system, pituitary and brain (Bole-Feysot et al. 1998, Goffin et al. 2002), and hence, when prolactin is elevated there is potential for a wide variety of systems to be influenced. In recent reviews (Grattan & Kokay 2008, Grattan & LeTissier 2015), we have proposed the hypothesis that the wide range of potential actions of prolactin in the body make some collective sense if considered within the context of the physiological hyperprolactinemic state of pregnancy and lactation. These are complex and demanding processes for a mother, requiring multiple diverse systems to undergo adaptive changes to facilitate her successful transition from the non-pregnant into the maternal state. A selection of these adaptive changes, and a summary of the evidence that prolactin might influence the adaptive response, are outlined in Table 1. Here, prolactin can be considered as interoceptive sensory information for the body, informing it of its new physiological state. The changes it induces are adaptive, which means that the functions are unlikely to completely fail in the absence of prolactin action, but they might not perform optimally. This would account for the absence of widespread adverse phenotype in the prolactin receptor knockout mice. It is appropriate to point out that many of the associations shown in Table 1 are, at this stage, correlative only, and comprehensive investigation proving that prolactin may be mediating a particular adaptive change will require significant further work. Nevertheless, we have found this to be a useful construct for understanding why prolactin might be influencing such a wide range of biological function. We used to be concerned by the question of, ‘Why would there be over 300 physiological actions of prolactin?’ Now, we can consider each of the different tissues that express the prolactin receptor and ask the question, ‘Why might this tissue need to change its function during lactation?’

Table 1

Role of prolactin in the maternal adaptation to pregnancy

Tissue or functionAdaptive change during pregnancyEvidence for possible role of prolactin?Selected references
Mammary gland/lactationBranching and alveolar development of mammary glandUnequivocal role, with lactation lost in Prlr−/− miceOrmandy et al. (1997) and Trott et al. (2012)
Milk secretion
Maternal behaviourRetrieval and nursing of pupsProlactin advances maternal responsiveness to pups in ratsRosenblatt (1967), Bridges et al. (1985, 1990, 1996) and Bridges & Ronsheim (1990)
Impairs behaviour in Prlr−/− miceLucas et al. (1998)
Adult neurogenesisIncreased neurogenesis in the subventricular zone of the maternal brainDriven by prolactin changes of pregnancyShingo et al. (2003)
Important for mood and behavioural changes post partumLarsen et al. (2008) and Larsen & Grattan (2010, 2012)
Pancreatic β cell/glucose homeostasisMaternal tissues become insulin resistant to promote glucose transfer to fetusProlactin receptors expressed in beta cells, and expression increased during pregnancyMoldrup et al. (1993), Sorenson & Stout (1995) and Brelje et al. (2004)
Expansion of beta cells in mother to increase insulin production, to prevent gestational diabetesProlactin stimulates insulin expression, secretion and beta cell proliferationKarnik et al. (2007)
Impaired glucose tolerance during pregnancy in Prlr+/− miceHuang et al. (2009), Kim et al. (2010), Rieck & Kaestner (2010), Schraenen et al. (2010) and Zhang et al. (2010)
Appetite regulationIncreased appetite and development of leptin resistanceProlactin stimulates food intake in non-pregnant animalsGerardo-Gettens et al. (1989), Sauvé & Woodside (1996, 2000) and Naef & Woodside (2007)
Fat deposition during pregnancy, mobilisation during lactationContributes to the development of leptin resistance during pregnancyAugustine & Grattan (2008), Ladyman (2008) and Ladyman et al. (2010)
Prolactin contributes to appetite drive during lactationWoodside et al. (2012)
Bone and calcium homeostasisIncreased calcium uptake and mobilisation of calcium stores for fetal skeletal growth and for milk productionProlactin receptors on osteoblasts and chondrocytesCharoenphandhu et al. (2010) and Wongdee et al. (2011)
Prolactin stimulates bone turnover
Prolactin promotes calcium absorption in the gut
ReproductionMaintenance of pregnancy (in rodents).Prolactin stimulates corpus luteum function in rodents, essential to maintain pregnancyGibori & Richards (1978) and Bachelot et al. (2009)
Loss of reproductive cycle during pregnancy, persisting during lactationHyperprolactinemia causes infertilityPatel & Bamigboye (2007)
Possible/likely involvement in lactational infertilityMcNeilly (2001a,b) and Liu et al. (2014)
Stress responsesReduced response to stress during late pregnancy and lactation, to minimise exposure of offspring to glucocorticoidsProlactin is anxiolytic and reduced stress responses in males and non-pregnant femalesShanks et al. (1999), Torner et al. (2001), Lonstein (2007) and Brunton & Russell (2008)
Role during pregnancy and lactation likely, but unprovenTorner & Neumann (2002) and Slattery & Neumann (2008)
Oxytocin secretionMarked change in firing pattern, generation of ‘burst’ firing to facilitate parturition and milk ejectionProlactin receptors on oxytocin neurons, and acute inhibitory effects on activityKokay et al. (2006) and Sapsford et al. (2011)
Stimulation of oxytocin gene expressionParker et al. (1991) and Ghosh & Sladek (1995a,b)
Prolactin secretionAltered feedback to facilitate prolactin secretionProlactin continues to stimulate TIDA neurons, but dopamine secretion is decreasedGrattan et al. (2008) and Romano et al. (2013)
Induction of enkephalin production in TIDAMerchenthaler et al. (1994) and Nahi & Arbogast (2003)

Comprehensive reviews of the wide range of actions of prolactin in the body are available elsewhere (Bole-Feysot et al. 1998, Freeman et al. 2000), as is our hypothesis regarding the role of prolactin in the physiological adaptation to pregnancy (Grattan & Kokay 2008, Grattan & LeTissier 2015), and hence, I will not go into detail here. In the final section of this review, I would like to briefly highlight three selected examples from recent research. The first of these, the metabolic functions of prolactin, nicely illustrates the context previously outlined that prolactin is acting in a number of different tissues and cell types in the mother to facilitate adaptation to pregnancy or lactation. The second example, looking at prolactin effects on fertility, highlights how functions of prolactin that might be considered adaptive in a lactating female, might be maladaptive should high prolactin occur at an inappropriate time. The third example asks the question, ‘What is prolactin doing in the male?’ This example is used to acknowledge the fact that some of the known functions of prolactin do not comfortably fit into the conceptual framework previously presented.

Metabolic function of prolactin

This is, perhaps, the best example of the pleiotropic role of prolactin (defined to mean a single gene product, prolactin, exerting multiple seemingly diverse actions). Prolactin receptors are expressed on multiple tissues involved in metabolic regulation, including adipose tissue, liver, pancreas and the brain. It appears to play a broad role in both pancreatic and adipose development. In adipose tissue, prolactin is essential in adipogenesis and adipocyte differentiation, as well as modulating lipid metabolism. It also regulates the secretion is several adipokines, including stimulation of leptin and inhibition of adiponectin production (Ben-Jonathan et al. 2006, Carre & Binart 2014). In the pancreas, it promotes growth of islets during development (Freemark et al. 2002), and increases insulin expression and glucose-stimulated insulin secretion (Sinha & Sorenson 1993, Brelje et al. 1994, 2004). It also increases expression of glucose transporter 2 and promotes glucose entry into the β-cells (Petryk et al. 2000), resulting in enhanced activity of glucose-sensitive enzymes such as glucokinase (Weinhaus et al. 2007). In both adipose tissue and pancreas, these actions are likely to be profoundly important during pregnancy and lactation. Lipid metabolism is altered, with lipid mobilisation from stores and utilisation in mamary gland promoted by prolactin (Barber et al. 1992). Adaptive changes in glucose homeostasis are also important in pregnancy (Rieck & Kaestner 2010). Maternal tissues develop insulin resistance to preferentially direct glucose to the fetal/placental compartment (Herrera 2000), and to ensure the maternal tissues continue to receive the nutrients required, there is increased demand for maternal insulin secretion, and glucose-stimulated insulin secretion increases. To adapt to this altered demand, there is significant proliferation of β-cells in the islets (Parsons et al. 1992), enhanced insulin synthesis (Bone & Taylor 1976), and decreased threshold for glucose-stimulated insulin secretion (Sorenson & Parsons 1985), with prolactin playing a critical adaptive role in promoting these changes (Newbern & Freemark 2011). Failure of this adaptive response results in gestational diabetes (Ramos-Roman 2011).

These peripheral actions of prolactin on metabolism are complemented by CNS actions of prolactin to promote appetite and potentially regulate glucose homeostasis. Systemic prolactin administration increases food intake in a variety of species (Moore et al. 1986, Gerardo-Gettens et al. 1989, Noel & Woodside 1993, Buntin et al. 1999), independent of potential effects on ovarian steroids (Noel & Woodside 1993, 2007, Sauvé & Woodside 1996). Thus, the elevated prolactin secretion is likely to contribute to the rapid increase in food intake during pregnancy (Shirley 1984, Ladyman & Grattan 2004, Ladyman et al. 2012) and the extreme hyperphagia of lactation (Woodside 2007, Woodside et al. 2012). Prolactin also induces functional leptin resistance, which would contribute to increased food intake (Naef & Woodside 2007, Augustine & Grattan 2008), potentially mediating the well-established leptin resistance of pregnancy (Grattan et al. 2007a, Augustine et al. 2008, Ladyman 2008, Ladyman et al. 2010). Prolactin receptors are found in many of the nuclei involved in the homeostatic regulation of food intake, including the arcuate, ventromedial and paraventricular nuclei (Bakowska & Morrell 1997, Pi & Grattan 1998b, Brown et al. 2010). However, prolactin receptors do not appear to be expressed in the arcuate neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons (Li et al. 1999, Chen & Smith 2004, Kokay & Grattan 2005) that regulate appetite. Hence, it seems likely that prolactin acts downstream of the arcuate neurons, such as at the paraventricular nucleus. Consistent with this hypothesis, localised injections of prolactin directly into the paraventricular nucleus stimulate food intake in a dose-dependent manner in female rats (Sauvé & Woodside 2000).

Thus, seemingly diverse actions of prolactin in multiple different cell types can be unified into a single adaptive function, which is metabolic adaptation to pregnancy, increasing energy availability to the mother and offspring. This is an example of the conceptual framework previously outlined, and it can be viewed as a positive, adaptive mechanism. Should hyperprolactinemia occur at an inappropriate time, however, then one might predict this could contribute to metabolic disorders. There is some evidence for this. While it is not universally observed, patients with hyperprolactinemia are prone to excessive weight gain (Creemers et al. 1991, Delgrange et al. 1999, Doknic et al. 2002, Baptista et al. 2004), and normalisation of prolactin levels using dopamine agonists is associated with weight loss (Greenman et al. 1998, Doknic et al. 2002, Galluzzi et al. 2005). Interestingly, genome-wide association studies have revealed that a common variant adjacent to the prolactin gene is associated with obesity (Meyre et al. 2009, Nilsson et al. 2011) suggesting that abnormalities in prolactin or prolactin signalling may contribute to human obesity.

Hyperprolactinemia and infertility

Hyperprolactinemia causes infertility in both males and females (Patel & Bamigboye 2007), and this provides an even more clear-cut example of a potentially adaptive function under certain conditions becoming clearly maladaptive in another situation. The mechanism by which prolactin inhibits the reproductive axis is not clear, but evidence suggests that prolactin impacts fertility through actions on GnRH neurons. In humans, hyperprolactinaemia is associated with a marked reduction in both the frequency and amplitude of LH pulses (Bohnet et al. 1976, Matsuzaki et al. 1994) indicative of a change in GnRH pulses, and the suppression of LH pulsatility can be reversed by reducing serum prolactin concentrations to normal (Moult et al. 1982). While prolactin could exert effects in either the pituitary or gonad, pulsatile GnRH replacement can reverse the infertility induced by hyperprolactinaemia (Polson et al. 1986, Matsuzaki et al. 1994, Lecomte et al. 1997), suggesting a prolactin-induced suppression of GnRH release is the proximal cause of infertility. Similarly, prolactin suppresses both the frequency and amplitude of LH pulses in male and female rats (Cohen-Becker et al. 1986, Fox et al. 1987, Park & Selmanoff 1991, Park et al. 1993) and measurements of GnRH secretion into the portal blood have revealed prolactin-induced suppression of GnRH release (Weber et al. 1983, Koike et al. 1984, 1991, Sarkar et al. 1992). Furthermore, hyperprolactinaemia has been shown to prevent the castration-induced increase in GnRH mRNA expression in rats (Selmanoff et al. 1991). Thus, although there is ample evidence that prolactin can act in the pituitary gland to suppress LH secretion (Smith 1978, 1982, Cheung 1983, Morel et al. 1994, Tortonese et al. 1998), in animal models, as in clinical studies, the primary cause of infertility appears to be the suppression of the activity of GnRH neurons. This effect of prolactin is unlikely to be mediated directly by an action on GnRH neurons, as the majority of these neurons do not express the prolactin receptor (Grattan et al. 2007b, Kokay et al. 2011). Thus, prolactin-induced inhibition of GnRH neurons must involve prolactin-sensitive afferents to these cells. Interestingly, most prolactin responsive neurons also express ERα (Furigo et al. 2014), so prolactin may share a common mechanism of regulating GnRH with the negative feedback pathway mediated by estradiol. As such, kisspeptin neurons have emerged as the most likely intermediate regulators.

Since first being identified as essential for puberty in humans (de Roux et al. 2003, Seminara et al. 2003), kisspeptin neurons are now recognised as critical parts of the circuit regulating activity of the GnRH neurons that control fertility (Pinilla et al. 2012). Kisspeptin neurons may have an important role in mediating the suppressive effect of prolactin on fertility. Kisspeptin is the most potent stimulator of GnRH neuronal activity yet identified (Han et al. 2005, Liu et al. 2008). In most mammalian species, there are two populations of kisspeptin neurons, with kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V) playing an essential role in enabling ovulation in rodents by activating GnRH neurons (Herbison 2008, Clarkson & Herbison 2009, Oakley et al. 2009), while kisspeptin neurons in the arcuate nucleus are thought to be involved in the regulation of the basal pulsatile secretion of GnRH (Li et al. 2009, Roseweir et al. 2009, Lehman et al. 2010, Navarro et al. 2011). Prolactin receptors are expressed in the majority of kisspeptin neurons in both populations (Kokay et al. 2011, Li et al. 2011), and prolactin has recently been shown to induce the phosphorylation of signal transducer and activator of transcription 5 (pSTAT5) in arcuate nucleus kisspeptin neurons in the rat (Araujo-Lopes et al. 2014) and rostral hypothalamic kisspeptin neurons in the mouse (Brown et al. 2014). Chronic infusion of prolactin in female mice abolished estrous cyclicity and suppressed global Gnrh and Kiss1 mRNA expression in the hypothalamus, while kisspeptin therapy restored estrous cycles in hyperprolactinemic mice (Sonigo et al. 2012), consistent with the hypothesis that prolactin-induced suppression of GnRH secretion is mediated by an inhibition of kisspeptin neurons.

Clearly, under most conditions, hyperprolactinemia represents a pathological condition with adverse consequences. During pregnancy and lactation, however, hyperprolactinemia is physiologically appropriate. When viewed from this context, an inhibitory action of prolactin on fertility during pregnancy and lactation would be highly adaptive, allowing the mother to focus energy on feeding her offspring, before investing resources in a further pregnancy (Valeggia & Ellison 2009). Lactation is associated with a period of infertility in most mammalian females, including women (McNeilly 2001a). In humans, this function serves as a critical regulator of population growth, spacing the timing of births to allow the mother to ration her metabolic investment across sequential pregnancies (Short 1976). Despite the extensive impact on mammalian reproductive physiology, our understanding of the mechanisms mediating lactational infertility remains incomplete (McNeilly 1994, 2001a,b). It is clear that suckling is the critical inhibitory signal (Tsukamura & Maeda 2001), and the principle cause of infertility is an almost-complete suppression of the pulsatile secretion of GnRH from the hypothalamus, the consequent loss of pituitary gonadotropin secretion and ovulation failure (Fox & Smith 1984). The pathways linking the suckling stimulus to the suppression of ovulation, however, are unclear. Kiss1 mRNA and protein levels are reduced in the arcuate nucleus of lactating rats associated with the suppression of pulsatile GnRH secretion during lactation (Yamada et al. 2007, 2012, Smith et al. 2010, True et al. 2011, Araujo-Lopes et al. 2014, Ladyman & Woodside 2014), and in both populations in the mouse (Brown et al. 2014). The RP3V kisspeptin population is harder to study in rats (Yamada et al. 2007, Desroziers et al. 2010), with reports of both Kiss1 mRNA remaining unchanged during lactation (Yamada et al. 2007) and of kisspeptin protein increasing while Kiss1 mRNA labeling decreased during lactation (Smith et al. 2010). More importantly, we have also shown that the reduction in kisspeptin expression results in complete loss of capacity for these neurons to activate GnRH neurons, even if they are stimulated exogenously (Liu et al. 2014). Given the similarity between the effect of suckling and the effect of prolactin, and the knowledge that suckling stimulates prolactin secretion, it seems likely that elevated prolactin during pregnancy and lactation contributes to the infertility of lactation, but this remains to be proven, and the relative roles of prolactin and/or suckling may be different in different species.

What does prolactin do in the male?

The hypothesis that most prolactin actions in the body can be tied to the adaptation to pregnancy and lactation clearly does not explain effects of prolactin in the male. Up to 40% of the male pituitary gland is dedicated to lactotrophs, suggesting that some function is retained in males, but knockout studies have not identified an essential function of prolactin. While there is no male equivalent of lactation, many of the other functions of prolactin in females can also be observed in males. For example, as in females, prolactin seems to be involved in parental behaviour in males, although the relative role that the mammalian father plays in parental care of offspring varies amongst species. In species where the male plays some role in rearing of the offspring, including humans (Gordon et al. 2010, Gettler et al. 2012), studies have found a association between prolactin and paternal care (Schradin & Anzenberger 1999), although the overall picture is unclear and controversial (Schradin 2007, Wynne-Edwards & Timonin 2007). Nevertheless, paternal recognition of offspring is consistent amongst most species. Pup-contact by male rats can lead to some forms of parental care behaviour and this is associated with an increase in serum prolactin, as well as increased expression of the long-form of the prolactin receptor in the brain (Sakaguchi et al. 1996). Further evidence for a direct role for prolactin in paternal recognition of offspring has been shown by studies of Prlr−/− fathers, who fail to distinguish adult offspring from non-offspring, possibly as a result of failure of prolactin-induced neurogensis in the sub-ventricular zone and the dentate gyrus (Mak & Weiss 2010).

As in females, pathological hyperprolactinemia causes infertility in males, but it is not clear that there is an adaptive role for prolactin in male reproduction. At lower levels, prolactin contributes a range of functions in the male reproductive tract, revealed by subtle reproductive deficits in the prolactin receptor deficient mice (Grattan & LeTissier 2015). In addition, many of the metabolic and immune functions of prolactin can be observed in males, but whether prolactin levels are ever sufficient for these effects to be of physiological significance is uncertain. Perhaps the most consistent stimulus for prolactin secretion in males is stress, but the functional consequences of this response are not well-understood (Gala 1990).

Conclusion

While Harris was correct in proposing that the brain controls prolactin secretion, the hypothalamo-prolactin axis proved itself to be quite different from all other pituitary systems. It remains the most complex and versatile of all of the hypothalamo-pituitary axes. Even if we just consider the relatively simple task of controlling milk production during lactation, there is much that remains to be understood, such as the possible role of one or more prolactin-releasing factors during the suckling stimulus, and the mechanism controlling the loss of dopamine production in the TIDA neurons and the changes in prolactin negative feedback. If we include the wide range of additional functions of prolactin, then the complexity becomes overwhelming. I have presented here a context to attempt to understand the pleiotropic roles of prolactin, arguing that many of the functions of prolactin can be unified into the overall task of maternal adaptation to pregnancy and lactation. Within this context, prolactin function promotes adaptive changes in a variety of body systems, but such actions can also be maladaptive, in a different context, if hyperprolactinemia occurs at an inappropriate time. This theoretical construct presents many new opportunities for generating testable hypotheses about prolactin function. But there are also many functions that do not fit easily into this construct, providing further opportunities for expanding our understanding. I anticipate that the coming availability of novel tools for investigating prolactin function, including gene-targeting approaches that allow conditional regulation of prolactin responsive cells, will provide the impetus for a new wave of research to enhance our understanding of this fascinating system. Sixty years on from Geoffrey Harris' prescient predictions, we still have a lot of work to do to understand the hypothalamo-prolactin system.

Footnote

This paper is part of a thematic review section on 60 years of neuroendocrinology. The Guest Editors for this section were Ashley Grossman and Clive Coen.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

Prof. D R Grattan is supported by research grants from the New Zealand Health Research Council and the Marsden Fund of the Royal Society of New Zealand.

References

  • AllenDLLowMJAllenRGBen-JonathanN1995Identification of two classes of prolactin-releasing factors in intermediate lobe tumors from transgenic mice. Endocrinology13630933099. (doi:10.1210/endo.136.7.7789336)

    • Search Google Scholar
    • Export Citation
  • AndersonGMBeijerPBangASFenwickMABunnSJGrattanDR2006aSuppression of prolactin-induced signal transducer and activator of transcription 5b signaling and induction of suppressors of cytokine signaling messenger ribonucleic acid in the hypothalamic arcuate nucleus of the rat during late pregnancy and lactation. Endocrinology14749965005. (doi:10.1210/en.2005-0755)

    • Search Google Scholar
    • Export Citation
  • AndersonSTBarclayJLFanningKJKustersDHWatersMJCurlewisJD2006bMechanisms underlying the diminished sensitivity to prolactin negative feedback during lactation: reduced STAT5 signalling and upregulation of cytokine-inducible SH2-domain-containing protein (CIS) expression in tuberoinfundibular dopaminergic neurons. Endocrinology14711951202. (doi:10.1210/en.2005-0905)

    • Search Google Scholar
    • Export Citation
  • AndersonGMKieserDCSteynFJGrattanDR2008Hypothalamic prolactin receptor messenger ribonucleic acid levels, prolactin signaling, and hyperprolactinemic inhibition of pulsatile luteinizing hormone secretion are dependent on estradiol. Endocrinology14915621570. (doi:10.1210/en.2007-0867)

    • Search Google Scholar
    • Export Citation
  • AndrewsZB2005Neuroendocrine regulation of prolactin secretion during late pregnancy: easing the transition into lactation. Journal of Neuroendocrinology17466473. (doi:10.1111/j.1365-2826.2005.01327.x)

    • Search Google Scholar
    • Export Citation
  • AndrewsZBGrattanDR2004The roles of dopamine and the neurointermediate lobe of the pituitary in the regulation of prolactin secretion during late pregnancy in rats. Journal of Neuroendocrinology16859865. (doi:10.1111/j.1365-2826.2004.01241.x)

    • Search Google Scholar
    • Export Citation
  • AndrewsZBKokayICGrattanDR2001Dissociation of prolactin secretion from tuberoinfundibular dopamine activity in late pregnant rats. Endocrinology14227192724. (doi:10.1210/endo.142.6.8196)

    • Search Google Scholar
    • Export Citation
  • AnnunziatoLMooreKE1978Prolactin in CSF selectively increases dopamine turnover in the median eminence. Life Sciences2220372042. (doi:10.1016/0024-3205(78)90551-9)

    • Search Google Scholar
    • Export Citation
  • Araujo-LopesRCramptonJRAquinoNSMirandaRMKokayICReisAMFranciCRGrattanDRSzawkaRE2014Prolactin regulates kisspeptin neurons in the arcuate nucleus to suppress LH secretion in female rats. Endocrinology15510101020. (doi:10.1210/en.2013-1889)

    • Search Google Scholar
    • Export Citation
  • ArbogastLABen-JonathanN1990The preovulatory prolactin surge is prolonged by a progesterone-dependent dopaminergic mechanism. Endocrinology126246252. (doi:10.1210/endo-126-1-246)

    • Search Google Scholar
    • Export Citation
  • ArbogastLAVoogtJL1991aHyperprolactinemia increases and hypoprolactinemia decreases tyrosine hydroxylase messenger ribonucleic acid levels in the arcuate nuclei, but not the substantia nigra or zona incerta. Endocrinology1289971005. (doi:10.1210/endo-128-2-997)

    • Search Google Scholar
    • Export Citation
  • ArbogastLAVoogtJL1991bMechanisms of tyrosine hydroxylase regulation during pregnancy: evidence for protein dephosphorylation during the prolactin surges. Endocrinology12925752582. (doi:10.1210/endo-129-5-2575)

    • Search Google Scholar
    • Export Citation
  • ArbogastLAVoogtJL1993Progesterone reverses the estradiol-induced decrease in tyrosine hydroxylase mRNA levels in the arcuate nucleus. Neuroendocrinology58501510. (doi:10.1159/000126583)

    • Search Google Scholar
    • Export Citation
  • ArbogastLAVoogtJL1994Progesterone suppresses tyrosine hydroxylase messenger ribonucleic acid levels in the arcuate nucleus on proestrus. Endocrinology135343350. (doi:10.1210/endo.135.1.7912184)

    • Search Google Scholar
    • Export Citation
  • ArbogastLAVoogtJL1997Prolactin (PRL) receptors are colocalized in dopaminergic neurons in fetal hypothalamic cell cultures: effect of PRL on tyrosine hydroxylase activity. Endocrinology13830163023. (doi:10.1210/endo.138.7.5227)

    • Search Google Scholar
    • Export Citation
  • AreyBJFreemanME1990Oxytocin, vasoactive-intestinal peptide, and serotonin regulate the mating-induced surges of prolactin secretion in the rat. Endocrinology126279284. (doi:10.1210/endo-126-1-279)

    • Search Google Scholar
    • Export Citation
  • AreyBJFreemanME1992aActivity of oxytocinergic neurons in the paraventricular nucleus mirrors the periodicity of the endogenous stimulatory rhythm regulating prolactin secretion. Endocrinology130126132. (doi:10.1210/endo.130.1.1727695)

    • Search Google Scholar
    • Export Citation
  • AreyBJFreemanME1992bActivity of vasoactive intestinal peptide and serotonin in the paraventricular nucleus reflects the periodicity of the endogenous stimulatory rhythm regulating prolactin secretion. Endocrinology131736742. (doi:10.1210/endo.131.2.1639019)

    • Search Google Scholar
    • Export Citation
  • AreyBJAverillRLFreemanME1989A sex-specific endogenous stimulatory rhythm regulating prolactin secretion. Endocrinology124119123. (doi:10.1210/endo-124-1-119)

    • Search Google Scholar
    • Export Citation
  • AreyBJKanyicskaBFreemanME1991The endogenous stimulatory rhythm regulating prolactin secretion is present in the lactating rat. Neuroendocrinology533540. (doi:10.1159/000125694)

    • Search Google Scholar
    • Export Citation
  • ArimuraADunnJDSchallyAV1972Effect of infusion of hypothalamic extracts on serum prolactin levels in rats treated with nembutal, CNS depressants or bearing hypothalamic lesions. Endocrinology90378383. (doi:10.1210/endo-90-2-378)

    • Search Google Scholar
    • Export Citation
  • AritaJKimuraF1987Direct inhibitory effect of long term estradiol treatment on dopamine synthesis in tuberoinfundibular dopaminergic neurons: in vitro studies using hypothalamic slices. Endocrinology121692698. (doi:10.1210/endo-121-2-692)

    • Search Google Scholar
    • Export Citation
  • AsaSLKellyMAGrandyDKLowMJ1999Pituitary lactotroph adenomas develop after prolonged lactotroph hyperplasia in dopamine D2 receptor-deficient mice. Endocrinology14053485355. (doi:10.1210/endo.140.11.7118)

    • Search Google Scholar
    • Export Citation
  • AugustineRAGrattanDR2008Induction of central leptin resistance in hyperphagic pseudopregnant rats by chronic prolactin infusion. Endocrinology14910491055. (doi:10.1210/en.2007-1018)

    • Search Google Scholar
    • Export Citation
  • AugustineRAKokayICAndrewsZBLadymanSRGrattanDR2003Quantitation of prolactin receptor mRNA in the maternal rat brain during pregnancy and lactation. Journal of Molecular Endocrinology31221232. (doi:10.1677/jme.0.0310221)

    • Search Google Scholar
    • Export Citation
  • AugustineRALadymanSRGrattanDR2008From feeding one to feeding many: hormone-induced changes in bodyweight homeostasis during pregnancy. Journal of Physiology586387397. (doi:10.1113/jphysiol.2007.146316)

    • Search Google Scholar
    • Export Citation
  • AverillRLGrattanDRNorrisSK1991Posterior pituitary lobectomy chronically attenuates the nocturnal surge of prolactin in early pregnancy. Endocrinology128705709. (doi:10.1210/endo-128-2-705)

    • Search Google Scholar
    • Export Citation
  • BachelotABeaufaronJServelNKedziaCMongetPKellyPAGiboriGBinartN2009Prolactin independent rescue of mouse corpus luteum life span: identification of prolactin and luteinizing hormone target genes. American Journal of Physiology. Endocrinology and Metabolism297E676E684.

    • Search Google Scholar
    • Export Citation
  • BakowskaJCMorrellJI1997Atlas of the neurons that express mRNA for the long form of the prolactin receptor in the forebrain of the female rat. Journal of Comparative Neurology386161177. (doi:10.1002/(SICI)1096-9861(19970922)386:2<161::AID-CNE1>3.0.CO;2-#)

    • Search Google Scholar
    • Export Citation
  • BaptistaTde BaptistaEALalondeJPlamondonJKinNMBeaulieuSJooberRRichardD2004Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection. Progress in Neuro-Psychopharmacology & Biological Psychiatry2813051311. (doi:10.1016/j.pnpbp.2004.08.001)

    • Search Google Scholar
    • Export Citation
  • BarberMCCleggRAFinleyEVernonRGFlintDJ1992The role of growth hormone, prolactin and insulin-like growth factors in the regulation of rat mammary gland and adipose tissue metabolism during lactation. Journal of Endocrinology135195202. (doi:10.1677/joe.0.1350195)

    • Search Google Scholar
    • Export Citation
  • BarracloughCASawyerCH1959Induction of pseudopregnancy in the rat by reserpine and chlorpromazine. Endocrinology65563571. (doi:10.1210/endo-65-4-563)

    • Search Google Scholar
    • Export Citation
  • BecquetDBoyerBRasolonjanaharyRBrueTGuillenSMorenoMFrancJLFrancois-BellanAM2014Evidence for an internal and functional circadian clock in rat pituitary cells. Molecular and Cellular Endocrinology382888898. (doi:10.1016/j.mce.2013.11.004)

    • Search Google Scholar
    • Export Citation
  • Ben-JonathanNHnaskoR2001Dopamine as a prolactin (PRL) inhibitor. Endocrine Reviews22724763. (doi:10.1210/edrv.22.6.0451)

  • Ben-JonathanNOliverCWeinerHJMicalRSPorterJC1977Dopamine in hypophysial portal plasma of the rat during the estrous cycle and throughout pregnancy. Endocrinology100452458. (doi:10.1210/endo-100-2-452)

    • Search Google Scholar
    • Export Citation
  • Ben-JonathanNNeillMAArbogastLAPetersLLHoeferMT1980Dopamine in hypophysial portal blood: relationship to circulating prolactin in pregnant and lactating rats. Endocrinology106690696. (doi:10.1210/endo-106-3-690)

    • Search Google Scholar
    • Export Citation
  • Ben-JonathanNHugoERBrandebourgTDLaPenseeCR2006Focus on prolactin as a metabolic hormone. Trends in Endocrinology and Metabolism17110116. (doi:10.1016/j.tem.2006.02.005)

    • Search Google Scholar
    • Export Citation
  • Ben-JonathanNLapenseeCRLapenseeEW2008What can we learn from rodents about prolactin in humans?Endocrine Reviews29141. (doi:10.1210/er.2007-0017)

    • Search Google Scholar
    • Export Citation
  • BerghornKALeWWShermanTGHoffmanGE2001Suckling stimulus suppresses messenger RNA for tyrosine hydroxylase in arcuate neurons during lactation. Journal of Comparative Neurology438423432. (doi:10.1002/cne.1325)

    • Search Google Scholar
    • Export Citation
  • BjorklundAMooreRYNobinASteneviU1973The organization of tubero-hypophyseal and reticulo-infundibular catecholamine neuron systems in the rat brain. Brain Research51171191. (doi:10.1016/0006-8993(73)90371-5)

    • Search Google Scholar
    • Export Citation
  • BlumMMcEwenBSRobertsJL1987Transcriptional analysis of tyrosine hydroxylase gene expression in the tuberoinfundibular dopaminergic neurons of the rat arcuate nucleus after estrogen treatment. Journal of Biological Chemistry262817821.

    • Search Google Scholar
    • Export Citation
  • BohnetHGDahlenHGWuttkeWSchneiderHP1976Hyperprolactinemic anovulatory syndrome. Journal of Clinical Endocrinology and Metabolism42132143. (doi:10.1210/jcem-42-1-132)

    • Search Google Scholar
    • Export Citation
  • Bole-FeysotCGoffinVEderyMBinartNKellyPA1998Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocrine Reviews19225268. (doi:10.1210/edrv.19.3.0334)

    • Search Google Scholar
    • Export Citation
  • BoneAJTaylorKW1976Metabolic adaptation to pregnancy shown by increased biosynthesis of insulin in islets of Langerhans isolated from pregnant rat. Nature262501502. (doi:10.1038/262501a0)

    • Search Google Scholar
    • Export Citation
  • BorgundvaagBKudlowJEMuellerSGGeorgeSR1992Dopamine receptor activation inhibits estrogen-stimulated transforming growth factor-α gene expression and growth in anterior pituitary, but not in uterus. Endocrinology13034533458. (doi:10.1210/endo.130.6.1534540)

    • Search Google Scholar
    • Export Citation
  • BosseRFumagalliFJaberMGirosBGainetdinovRRWetselWCMissaleCCaronMG1997Anterior pituitary hypoplasia and dwarfism in mice lacking the dopamine transporter. Neuron19127138. (doi:10.1016/S0896-6273(00)80353-0)

    • Search Google Scholar
    • Export Citation
  • BreljeTCParsonsJASorensonRL1994Regulation of islet β-cell proliferation by prolactin in rat islets. Diabetes43263273. (doi:10.2337/diab.43.2.263)

    • Search Google Scholar
    • Export Citation
  • BreljeTCStoutLEBhagrooNVSorensonRL2004Distinctive roles for prolactin and growth hormone in the activation of signal transducer and activator of transcription 5 in pancreatic islets of Langerhans. Endocrinology14541624175. (doi:10.1210/en.2004-0201)

    • Search Google Scholar
    • Export Citation
  • BridgesRSRonsheimPM1990Prolactin (PRL) regulation of maternal behavior in rats: bromocriptine treatment delays and PRL promotes the rapid onset of behavior. Endocrinology126837848. (doi:10.1210/endo-126-2-837)

    • Search Google Scholar
    • Export Citation
  • BridgesRSDiBiaseRLoundesDDDohertyPC1985Prolactin stimulation of maternal behavior in female rats. Science227782784. (doi:10.1126/science.3969568)

    • Search Google Scholar
    • Export Citation
  • BridgesRSNumanMRonsheimPMMannPELupiniCE1990Central prolactin infusions stimulate maternal behavior in steroid-treated, nulliparous female rats. PNAS8780038007. (doi:10.1073/pnas.87.20.8003)

    • Search Google Scholar
    • Export Citation
  • BridgesRSRobertsonMCShiuRPCFriesenHGStuerAMMannPE1996Endocrine communication between conceptus and mother: placental lactogen stimulation of maternal behavior. Neuroendocrinology645764. (doi:10.1159/000127098)

    • Search Google Scholar
    • Export Citation
  • BrownRSKokayICHerbisonAEGrattanDR2010Distribution of prolactin-responsive neurons in the mouse forebrain. Journal of Comparative Neurology51892102. (doi:10.1002/cne.22208)

    • Search Google Scholar
    • Export Citation
  • BrownRSPietRHerbisonAEGrattanDR2012Differential actions of prolactin on electrical activity and intracellular signal transduction in hypothalamic neurons. Endocrinology15323752384. (doi:10.1210/en.2011-2005)

    • Search Google Scholar
    • Export Citation
  • BrownRSHerbisonAEGrattanDR2014Prolactin regulation of kisspeptin neurones in the mouse brain and its role in the lactation-induced suppression of kisspeptin expression. Journal of Neuroendocrinology26898908. (doi:10.1111/jne.12223)

    • Search Google Scholar
    • Export Citation
  • BruntonPJRussellJA2008The expectant brain: adapting for motherhood. Nature Reviews. Neuroscience91125.

  • BuntinJDHnaskoRMZuzickPH1999Role of the ventromedial hypothalamus in prolactin-induced hyperphagia in ring doves. Physiology & Behavior66255261. (doi:10.1016/S0031-9384(98)00288-1)

    • Search Google Scholar
    • Export Citation
  • CarreNBinartN2014Prolactin and adipose tissue. Biochimie971621. (doi:10.1016/j.biochi.2013.09.023)

  • CharoenphandhuNWongdeeKKrishnamraN2010Is prolactin the cardinal calciotropic maternal hormone?Trends in Endocrinology and Metabolism21395401. (doi:10.1016/j.tem.2010.02.002)

    • Search Google Scholar
    • Export Citation
  • ChenPSmithMS2004Regulation of hypothalamic neuropeptide Y messenger ribonucleic acid expression during lactation: role of prolactin. Endocrinology145823829. (doi:10.1210/en.2003-1255)

    • Search Google Scholar
    • Export Citation
  • CheungCY1983Prolactin suppresses luteinizing hormone secretion and pituitary responsiveness to luteinizing hormone-releasing hormone by a direct action at the anterior pituitary. Endocrinology113632638. (doi:10.1210/endo-113-2-632)

    • Search Google Scholar
    • Export Citation
  • ClarksonJHerbisonAE2009Oestrogen, kisspeptin, GPR54 and the pre-ovulatory luteinising hormone surge. Journal of Neuroendocrinology21305311. (doi:10.1111/j.1365-2826.2009.01835.x)

    • Search Google Scholar
    • Export Citation
  • Cohen-BeckerIRSelmanoffMWisePM1986Hyperprolactinemia alters the frequency and amplitude of pulsatile luteinizing hormone secretion in the ovariectomized rat. Neuroendocrinology42328333. (doi:10.1159/000124459)

    • Search Google Scholar
    • Export Citation
  • CowieATTindalJSBensonGK1960Pituitary grafts and milk secretion in hypophysectomized rats. Journal of Endocrinology21115123. (doi:10.1677/joe.0.0210115)

    • Search Google Scholar
    • Export Citation
  • CramerOMParkerCRJrPorterJC1979Estrogen inhibition of dopamine release into hypophysial portal blood. Endocrinology104419422. (doi:10.1210/endo-104-2-419)

    • Search Google Scholar
    • Export Citation
  • CreemersLBZelissenPMvan 't VerlaatJWKoppeschaarHP1991Prolactinoma and body weight: a retrospective study. Acta Endocrinologica125392396. (doi:10.1530/acta.0.1250392)

    • Search Google Scholar
    • Export Citation
  • CrowleyWR2015Neuroendocrine regulation of lactation and milk production. Comprehensive Physiology5255291. (doi:10.1002/cphy.c140029)

  • CservenakMBodnarIUsdinTBPalkovitsMNagyGMDobolyiA2010Tuberoinfundibular peptide of 39 residues is activated during lactation and participates in the suckling-induced prolactin release in rat. Endocrinology15158305840. (doi:10.1210/en.2010-0767)

    • Search Google Scholar
    • Export Citation
  • CusanLDupontAKledzikGSLabrieFCoyDHSchallyAV1977Potent prolactin and growth hormone releasing activity of more analogues of Met-enkephalin. Nature268544547. (doi:10.1038/268544a0)

    • Search Google Scholar
    • Export Citation
  • De GreefWJNeillJD1979Dopamine levels in hypophysial stalk plasma of the rat during surges of prolactin secretion induced by cervical stimulation. Endocrinology10510931099. (doi:10.1210/endo-105-5-1093)

    • Search Google Scholar
    • Export Citation
  • De LeanALabrieF1977Sensitizing effect of treatment with estrogens on TSH response to TRH in male rats. American Journal of Physiology233E235E239.

    • Search Google Scholar
    • Export Citation
  • DelgrangeEDonckierJMaiterD1999Hyperprolactinaemia as a reversible cause of weight gain in male patients?Clinical Endocrinology50271. (doi:10.1046/j.1365-2265.1999.00700.x)

    • Search Google Scholar
    • Export Citation
  • DemarestKTMcKayDWRiegleGDMooreKE1983Biochemical indices of tuberoinfundibular dopaminergic neuronal activity during lactation: a lack of response to prolactin. Neuroendocrinology36130137. (doi:10.1159/000123449)

    • Search Google Scholar
    • Export Citation
  • DemarestKTRiegleGDMooreKE1984aProlactin-induced activation of tuberoinfundibular dopaminergic neurons: evidence for both a rapid ‘tonic’ and a delayed ‘induction’ component. Neuroendocrinology38467475. (doi:10.1159/000123935)

    • Search Google Scholar
    • Export Citation
  • DemarestKTRiegleGDMooreKE1984bLong-term treatment with estradiol induces reversible alterations in tuberoinfundibular dopaminergic neurons: a decreased responsiveness to prolactin. Neuroendocrinology39193200. (doi:10.1159/000123979)

    • Search Google Scholar
    • Export Citation
  • DemarestKTRiegleGDMooreKE1986The rapid ‘tonic’ and the delayed ‘induction’ components of the prolactin-induced activation of tuberoinfundibular dopaminergic neurons following the systemic administration of prolactin. Neuroendocrinology43291299. (doi:10.1159/000124543)

    • Search Google Scholar
    • Export Citation
  • DeMariaJELivingstoneJDFreemanME1998Characterization of the dopaminergic input to the pituitary gland throughout the estrous cycle of the rat. Neuroendocrinology67377383. (doi:10.1159/000054336)

    • Search Google Scholar
    • Export Citation
  • DeMariaJELerantAAFreemanME1999Prolactin activates all three populations of hypothalamic neuroendocrine dopaminergic neurons in ovariectomized rats. Brain Research837236241. (doi:10.1016/S0006-8993(99)01667-4)

    • Search Google Scholar
    • Export Citation
  • DeMariaJELivingstoneJDFreemanME2000Ovarian steroids influence the activity of neuroendocrine dopaminergic neurons. Brain Research879139147. (doi:10.1016/S0006-8993(00)02763-3)

    • Search Google Scholar
    • Export Citation
  • DempseyEWUotilaUU1940The effect of pituitary stalk section upon reproductive phenomena in the female rat. Endocrinology27573579. (doi:10.1210/endo-27-4-573)

    • Search Google Scholar
    • Export Citation
  • DesroziersEMikkelsenJSimonneauxVKellerMTilletYCaratyAFranceschiniI2010Mapping of kisspeptin fibres in the brain of the pro-oestrous rat. Journal of Neuroendocrinology2211011112. (doi:10.1111/j.1365-2826.2010.02053.x)

    • Search Google Scholar
    • Export Citation
  • DobolyiA2011Novel potential regulators of maternal adaptations during lactation: tuberoinfundibular peptide 39 and amylin. Journal of Neuroendocrinology2310021008. (doi:10.1111/j.1365-2826.2011.02127.x)

    • Search Google Scholar
    • Export Citation
  • DobolyiADimitrovEPalkovitsMUsdinTB2012The neuroendocrine functions of the parathyroid hormone 2 receptor. Frontiers in Endocrinology3121. (doi:10.3389/fendo.2012.00121)

    • Search Google Scholar
    • Export Citation
  • DoknicMPekicSZarkovicMMedic-StojanoskaMDieguezCCasanuevaFPopovicV2002Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine. European Journal of Endocrinology/European Federation of Endocrine Societies1477784. (doi:10.1530/eje.0.1470077)

    • Search Google Scholar
    • Export Citation
  • EikenburgDCRavitzAJGudelskyGAMooreKE1977Effects of estrogen on prolactin and tuberoinfundibular dopaminergic neurons. Journal of Neural Transmission40235244. (doi:10.1007/BF01257017)

    • Search Google Scholar
    • Export Citation
  • ElsholtzHPLewAMAlbertPRSundmarkVC1991Inhibitory control of prolactin and Pit-1 gene promoters by dopamine. Dual signaling pathways required for D2 receptor-regulated expression of the prolactin gene. Journal of Biological Chemistry2662291922925.

    • Search Google Scholar
    • Export Citation
  • EnjalbertARubergMArancibiaSPriamMKordonC1979Endogenous opiates block dopamine inhibition of prolactin secretion in vitro. Nature280595597. (doi:10.1038/280595a0)

    • Search Google Scholar
    • Export Citation
  • EverettJW1954Luteotrophic function of autographs of the rat hypophysis. Endocrinology54685690. (doi:10.1210/endo-54-6-685)

  • FeherPOlahMBodnarIHechtlDBacskayIJuhaszBNagyGMVecsernyesM2010Dephosphorylation/inactivation of tyrosine hydroxylase at the median eminence of the hypothalamus is required for suckling-induced prolactin and adrenocorticotrop hormone responses. Brain Research Bulletin82141145. (doi:10.1016/j.brainresbull.2010.02.006)

    • Search Google Scholar
    • Export Citation
  • FinkG1988Oestrogen and progesterone interactions in the control of gonadotrophin and prolactin secretion. Journal of Steroid Biochemistry30169178. (doi:10.1016/0022-4731(88)90090-8)

    • Search Google Scholar
    • Export Citation
  • FliestraRJVoogtJL1997Lactogenic hormones of the placenta and pituitary inhibit suckling-induced prolactin (PRL) release but not the ante-partum PRL surge. Proceedings of the Society for Experimental Biology and Medicine214258264. (doi:10.3181/00379727-214-44094)

    • Search Google Scholar
    • Export Citation
  • FoxSRSmithMS1984The suppression of pulsatile luteinizing hormone secretion during lactation in the rat. Endocrinology11520452051. (doi:10.1210/endo-115-6-2045)

    • Search Google Scholar
    • Export Citation
  • FoxSRHoeferMTBartkeASmithMS1987Suppression of pulsatile LH secretion, pituitary GnRH receptor content and pituitary responsiveness to GnRH by hyperprolactinemia in the male rat. Neuroendocrinology46350359. (doi:10.1159/000124844)

    • Search Google Scholar
    • Export Citation
  • FoxSRHarlanREShiversBDPfaffDW1990Chemical characterization of neuroendocrine targets for progesterone in the female rat brain and pituitary. Neuroendocrinology51276283. (doi:10.1159/000125350)

    • Search Google Scholar
    • Export Citation
  • FreemanMEKanyicskaBLerantANagyG2000Prolactin: structure, function, and regulation of secretion. Physiological Reviews8015231631.

  • FreemarkMAvrilIFleenorDDriscollPPetroAOparaEKendallWOdenJBridgesSBinartN2002Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance. Endocrinology14313781385. (doi:10.1210/endo.143.4.8722)

    • Search Google Scholar
    • Export Citation
  • FurigoICKimKWNagaishiVSRamos-LoboAMde AlencarAPedrosoJAMetzgerMDonatoJJr2014Prolactin-sensitive neurons express estrogen receptor-α and depend on sex hormones for normal responsiveness to prolactin. Brain Research15664759. (doi:10.1016/j.brainres.2014.04.018)

    • Search Google Scholar
    • Export Citation
  • FuxeK1963Cellular localisations of monoamines in the median eminence and in the infundibular stem of some mammals. Acta Physiologica Scandinavica58383384. (doi:10.1111/j.1748-1716.1963.tb02662.x)

    • Search Google Scholar
    • Export Citation
  • FuxeK1964Cellular localization of monoamines in the median eminence and the infundibular stem of some mammals. Zeitschrift für Zellforschung und Mikroskopische Anatomie. Abteilung Histochemie61710724.

    • Search Google Scholar
    • Export Citation
  • GalaRR1990The physiology and mechanisms of the stress-induced changes in prolactin secretion in the rat. Life Sciences4614071420. (doi:10.1016/0024-3205(90)90456-2)

    • Search Google Scholar
    • Export Citation
  • GalluzziFSaltiRStagiSLa CauzaFChiarelliF2005Reversible weight gain and prolactin levels – long-term follow-up in childhood. Journal of Pediatric Endocrinology & Metabolism18921924. (doi:10.1515/JPEM.2005.18.9.921)

    • Search Google Scholar
    • Export Citation
  • Gerardo-GettensTMooreBJSternJSHorwitzBA1989Prolactin stimulates food intake in a dose-dependent manner. American Journal of Physiology256R276R280.

    • Search Google Scholar
    • Export Citation
  • GettlerLTMcDadeTWFeranilABKuzawaCW2012Prolactin, fatherhood, and reproductive behavior in human males. American Journal of Physical Anthropology148362370. (doi:10.1002/ajpa.22058)

    • Search Google Scholar
    • Export Citation
  • GhoshRSladekCD1995aProlactin modulates oxytocin mRNA during lactation by its action on the hypothalamo-neurohypophyseal axis. Brain Research6722428.

    • Search Google Scholar
    • Export Citation
  • GhoshRSladekCD1995bRole of prolactin and gonadal steroids in regulation of oxytocin mRNA during lactation. American Journal of Physiology269E76E84.

    • Search Google Scholar
    • Export Citation
  • GibbsDMNeillJD1978Dopamine levels in hypophysial stalk blood in the rat are sufficient to inhibit prolactin secretion in vivo. Endocrinology10218951900. (doi:10.1210/endo-102-6-1895)

    • Search Google Scholar
    • Export Citation
  • GiboriGRichardsJS1978Dissociation of two distinct luteotropic effects of prolactin: regulation of luteinizing hormone-receptor content and progesterone secretion during pregnancy. Endocrinology102767774.

    • Search Google Scholar
    • Export Citation
  • GoffinVBinartNTourainePKellyPA2002Prolactin: the new biology of an old hormone. Annual Review of Physiology644767. (doi:10.1146/annurev.physiol.64.081501.131049)

    • Search Google Scholar
    • Export Citation
  • GordonIZagoory-SharonOLeckmanJFFeldmanR2010Prolactin, oxytocin, and the development of paternal behavior across the first six months of fatherhood. Hormones and Behavior58513518. (doi:10.1016/j.yhbeh.2010.04.007)

    • Search Google Scholar
    • Export Citation
  • GoudreauJLLindleySELookinglandKJMooreKE1992Evidence that hypothalamic periventricular dopamine neurons innervate the intermediate lobe of the rat pituitary. Neuroendocrinology56100105. (doi:10.1159/000126214)

    • Search Google Scholar
    • Export Citation
  • GrattanDR2001The actions of prolactin in the brain during pregnancy and lactation. Progress in Brain Research133153171. (doi:10.1016/S0079-6123(01)33012-1)

    • Search Google Scholar
    • Export Citation
  • GrattanDRAverillRL1990Effect of ovarian steroids on a nocturnal surge of prolactin secretion that precedes parturition in the rat. Endocrinology12611991205. (doi:10.1210/endo-126-2-1199)

    • Search Google Scholar
    • Export Citation
  • GrattanDRAverillRL1991Intrahypothalamic pituitary grafts elevate prolactin in the cerebrospinal fluid and attenuate prolactin release following ether stress. Proceedings of the Society for Experimental Biology and Medicine1964246. (doi:10.3181/00379727-196-43161)

    • Search Google Scholar
    • Export Citation
  • GrattanDRAverillRL1995Absence of short-loop autoregulation of prolactin during late pregnancy in the rat. Brain Research Bulletin36413416. (doi:10.1016/0361-9230(94)00216-N)

    • Search Google Scholar
    • Export Citation
  • GrattanDRKokayIC2008Prolactin: a pleiotropic neuroendocrine hormone. Journal of Neuroendocrinology20752763. (doi:10.1111/j.1365-2826.2008.01736.x)

    • Search Google Scholar
    • Export Citation
  • Grattan DR & LeTissier P 2015 Hypothalamic control of prolactin secretion and the multiple reproductive functions of prolactin. In Knobil and Neill's Physiology of Reproduction 4th edn pp 469–526. Eds TM Plant & AJ Zelesnik. Amsterdam: Elsevier.

  • GrattanDRXuJMcLachlanMJKokayICBunnSJHoveyRCDaveyHW2001Feedback regulation of PRL secretion is mediated by the transcription factor, signal transducer, and activator of transcription 5b. Endocrinology14239353940. (doi:10.1210/endo.142.9.8385)

    • Search Google Scholar
    • Export Citation
  • GrattanDRLadymanSRAugustineRA2007aHormonal induction of leptin resistance during pregnancy. Physiology & Behavior91366374. (doi:10.1016/j.physbeh.2007.04.005)

    • Search Google Scholar
    • Export Citation
  • GrattanDRJasoniCLLiuXAndersonGMHerbisonAE2007bProlactin regulation of gonadotropin-releasing hormone neurons to suppress luteinizing hormone secretion in mice. Endocrinology14843444351. (doi:10.1210/en.2007-0403)

    • Search Google Scholar
    • Export Citation
  • GrattanDRSteynFJKokayICAndersonGMBunnSJ2008Pregnancy-induced adaptation in the neuroendocrine control of prolactin secretion. Journal of Neuroendocrinology20497507. (doi:10.1111/j.1365-2826.2008.01661.x)

    • Search Google Scholar
    • Export Citation
  • GreenmanYTordjmanKSternN1998Increased body weight associated with prolactin secreting pituitary adenomas: weight loss with normalization of prolactin levels. Clinical Endocrinology48547553. (doi:10.1046/j.1365-2265.1998.00403.x)

    • Search Google Scholar
    • Export Citation
  • GregersonKA2003Functional expression of the dopamine-activated K(+) current in lactotrophs during the estrous cycle in female rats: correlation with prolactin secretory responses. Endocrine206774. (doi:10.1385/ENDO:20:1-2:67)

    • Search Google Scholar
    • Export Citation
  • GregersonKA2006Prolactin: structure, function, and regulation of secretion. In Knobil and Neill's Physiology of Reproduction pp 17031726. Ed. NeillJD. Amsterdam: Elsevier.

    • Search Google Scholar
    • Export Citation
  • GregersonKAGolesorkhiNChuknyiskaR1994Stimulation of prolactin release by dopamine withdrawal: role of membrane hyperpolarization. American Journal of Physiology267E781E788.

    • Search Google Scholar
    • Export Citation
  • GudelskyGAPorterJC1979Release of newly synthesized dopamine into the hypophysial portal vasculature of the rat. Endocrinology104583587. (doi:10.1210/endo-104-3-583)

    • Search Google Scholar
    • Export Citation
  • GunnetJWFreemanME1983The mating-induced release of prolactin: a unique neuroendocrine response. Endocrine Reviews44461. (doi:10.1210/edrv-4-1-44)

    • Search Google Scholar
    • Export Citation
  • HanSKGottschMLLeeKJPopaSMSmithJTJakawichSKCliftonDKSteinerRAHerbisonAE2005Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. Journal of Neuroscience251134911356. (doi:10.1523/JNEUROSCI.3328-05.2005)

    • Search Google Scholar
    • Export Citation
  • HarrisGW1948Neural control of the pituitary gland. Physiological Reviews28139179.

  • HentgesSTLowMJ2002Ovarian dependence for pituitary tumorigenesis in D2 dopamine receptor-deficient mice. Endocrinology14345364543. (doi:10.1210/en.2002-220421)

    • Search Google Scholar
    • Export Citation
  • HerbisonAE2008Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: the case for the rostral periventricular area of the third ventricle (RP3V). Brain Research Reviews57277287. (doi:10.1016/j.brainresrev.2007.05.006)

    • Search Google Scholar
    • Export Citation
  • HerreraE2000Metabolic adaptations in pregnancy and their implications for the availability of substrates to the fetus. European Journal of Clinical Nutrition54 (Suppl 1) S47S51. (doi:10.1038/sj.ejcn.1600984)

    • Search Google Scholar
    • Export Citation
  • HnaskoRKhuranaSShacklefordNSteinmetzRLowMJBen-JonathanN1997Two distinct pituitary cell lines from mouse intermediate lobe tumors: a cell that produces prolactin-regulating factor and a melanotroph. Endocrinology13855895596. (doi:10.1210/endo.138.12.5656)

    • Search Google Scholar
    • Export Citation
  • HokfeltTFuxeK1972Effects of prolactin and ergot alkaloids on the tubero-infundibular dopamine (DA) neurons. Neuroendocrinology9100122. (doi:10.1159/000122042)

    • Search Google Scholar
    • Export Citation
  • HolzbauerMRackeK1985The dopaminergic innervation of the intermediate lobe and of the neural lobe of the pituitary gland. Medical Biology6397116.

    • Search Google Scholar
    • Export Citation
  • HorsemanND1995Prolactin, proliferation, and protooncogenes. Endocrinology13652495251. (doi:10.1210/endo.136.12.7588267)

  • HoveyRCTrottJFGinsburgEGoldharASasakiMMFountainSJSundararajanKVonderhaarBK2001Transcriptional and spatiotemporal regulation of prolactin receptor mRNA and cooperativity with progesterone receptor function during ductal branch growth in the mammary gland. Developmental Dynamics222192205. (doi:10.1002/dvdy.1179)

    • Search Google Scholar
    • Export Citation
  • HuangCSniderFCrossJC2009Prolactin receptor is required for normal glucose homeostasis and modulation of β-cell mass during pregnancy. Endocrinology15016181626. (doi:10.1210/en.2008-1003)

    • Search Google Scholar
    • Export Citation
  • Huerta-OcampoIChristianHCThompsonNMEl-KastiMMWellsT2005The Intermediate lactotroph: a morphologically distinct, ghrelin-responsive pituitary cell in the dwarf (dw/dw) rat. Endocrinology14650125023. (doi:10.1210/en.2005-0335)

    • Search Google Scholar
    • Export Citation
  • IshidaMMitsuiTYamakawaKSugiyamaNTakahashiWShimuraHEndoTKobayashiTAritaJ2007Involvement of cAMP response element-binding protein in the regulation of cell proliferation and the prolactin promoter of lactotrophs in primary culture. American Journal of Physiology. Endocrinology and Metabolism293E1529E1537. (doi:10.1152/ajpendo.00028.2007)

    • Search Google Scholar
    • Export Citation
  • JohnstonCADemarestKTMooreKE1980Cycloheximide disrupts the prolactin-mediated stimulation of dopamine synthesis in tuberoinfundibular neurons. Brain Research195236240. (doi:10.1016/0006-8993(80)90883-5)

    • Search Google Scholar
    • Export Citation
  • JonesEENaftolinF1990Estrogen effects on the tuberoinfundibular dopaminergic system in the female rat brain. Brain Research5108491. (doi:10.1016/0006-8993(90)90730-Y)

    • Search Google Scholar
    • Export Citation
  • KamberiIAMicalRSPorterJC1970Prolactin-inhibiting activity in hypophysial stalk blood and elevation by dopamine. Experientia2611501151. (doi:10.1007/BF02112730)

    • Search Google Scholar
    • Export Citation
  • KanematsuSSawyerCH1973Elevation of plasma prolactin after hypophysial stalk section in the rat. Endocrinology93238241. (doi:10.1210/endo-93-1-238)

    • Search Google Scholar
    • Export Citation
  • KanematsuSHilliardJSawyerCH1963Effect of reserpine on pituitary prolactin content and its hypothalamic site of action in the rabbit. Acta Endocrinologica44467474. (doi:10.1530/acta.0.0440467)

    • Search Google Scholar
    • Export Citation
  • KansraSYamagataSSneadeLFosterLBen-JonathanN2005Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release. Molecular and Cellular Endocrinology2392736. (doi:10.1016/j.mce.2005.04.008)

    • Search Google Scholar
    • Export Citation
  • KansraSChenSBangaruMLSneadeLDunckleyJABen-JonathanN2010Selective estrogen receptor down-regulator and selective estrogen receptor modulators differentially regulate lactotroph proliferation. PLoS ONE5e10060. (doi:10.1371/journal.pone.0010060)

    • Search Google Scholar
    • Export Citation
  • KarnikSKChenHMcLeanGWHeitJJGuXZhangAYFontaineMYenMHKimSK2007Menin controls growth of pancreatic β-cells in pregnant mice and promotes gestational diabetes mellitus. Science318806809. (doi:10.1126/science.1146812)

    • Search Google Scholar
    • Export Citation
  • KellyMARubinsteinMAsaSLZhangGSaezCBunzowJRAllenRGHnaskoRBen-JonathanNGrandyDK1997Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron19103113. (doi:10.1016/S0896-6273(00)80351-7)

    • Search Google Scholar
    • Export Citation
  • KimHToyofukuYLynnFCChakEUchidaTMizukamiHFujitaniYKawamoriRMiyatsukaTKosakaY2010Serotonin regulates pancreatic β cell mass during pregnancy. Nature Medicine16804808. (doi:10.1038/nm.2173)

    • Search Google Scholar
    • Export Citation
  • KoikeKAonoTMiyakeATasakaKChataniFKurachiK1984Effect of pituitary transplants on the LH-RH concentrations in the medial basal hypothalamus and hypophyseal portal blood. Brain Research301253258. (doi:10.1016/0006-8993(84)91093-X)

    • Search Google Scholar
    • Export Citation
  • KoikeKMiyakeAAonoTSakumotoTOhmichiMYamaguchiMTanizawaO1991Effect of prolactin on the secretion of hypothalamic GnRH and pituitary gonadotropins. Hormone Research35512. (doi:10.1159/000181921)

    • Search Google Scholar
    • Export Citation
  • KokayICGrattanDR2005Expression of mRNA for prolactin receptor (long form) in dopamine and pro-opiomelanocortin neurones in the arcuate nucleus of non-pregnant and lactating rats. Journal of Neuroendocrinology17827835. (doi:10.1111/j.1365-2826.2005.01374.x)

    • Search Google Scholar
    • Export Citation
  • KokayICBullPMDavisRLLudwigMGrattanDR2006Expression of the long form of the prolactin receptor in magnocellular oxytocin neurons is associated with specific prolactin regulation of oxytocin neurons. American Journal of Physiology: Regulatory Integrative and Comparative Physiology290R1216R1225.

    • Search Google Scholar
    • Export Citation
  • KokayICPetersenSLGrattanDR2011Identification of prolactin-sensitive GABA and kisspeptin neurons in regions of the rat hypothalamus involved in the control of fertility. Endocrinology152526535. (doi:10.1210/en.2010-0668)

    • Search Google Scholar
    • Export Citation
  • LadymanSR2008Leptin resistance during pregnancy in the rat. Journal of Neuroendocrinology20269277. (doi:10.1111/j.1365-2826.2007.01628.x)

    • Search Google Scholar
    • Export Citation
  • LadymanSRGrattanDR2004Region-specific reduction in leptin-induced phosphorylation of signal transducer and activator of transcription-3 (STAT3) in the rat hypothalamus is associated with leptin resistance during pregnancy. Endocrinology14537043711. (doi:10.1210/en.2004-0338)

    • Search Google Scholar
    • Export Citation
  • LadymanSRWoodsideB2014Food restriction during lactation suppresses Kiss1 mRNA expression and kisspeptin-stimulated LH release in rats. Reproduction147743751. (doi:10.1530/REP-13-0426)

    • Search Google Scholar
    • Export Citation
  • LadymanSRAugustineRAGrattanDR2010Hormone interactions regulating energy balance during pregnancy. Journal of Neuroendocrinology22805817. (doi:10.1111/j.1365-2826.2010.02017.x)

    • Search Google Scholar
    • Export Citation
  • LadymanSRFieldwickDMGrattanDR2012Suppression of leptin-induced hypothalamic JAK/STAT signalling and feeding response during pregnancy in the mouse. Reproduction1448390. (doi:10.1530/REP-12-0112)

    • Search Google Scholar
    • Export Citation
  • LarsenCMGrattanDR2010Prolactin-induced mitogenesis in the subventricular zone of the maternal brain during early pregnancy is essential for normal postpartum behavioral responses in the mother. Endocrinology15138053814. (doi:10.1210/en.2009-1385)

    • Search Google Scholar
    • Export Citation
  • LarsenCMGrattanDR2012Prolactin, neurogenesis, and maternal behaviors. Brain Behavior and Immunity26201209. (doi:10.1016/j.bbi.2011.07.233)

    • Search Google Scholar
    • Export Citation
  • LarsenCMKokayICGrattanDR2008Male pheromones initiate prolactin-induced neurogenesis and advance maternal behavior in female mice. Hormones and Behavior53509517. (doi:10.1016/j.yhbeh.2007.11.020)

    • Search Google Scholar
    • Export Citation
  • LecomtePLecomteCLansacJGallierJSonierCBSimonettaC1997Pregnancy after intravenous pulsatile gonadotropin-releasing hormone in a hyperprolactinaemic woman resistant to treatment with dopamine agonists. European Journal of Obstetrics Gynecology and Reproductive Biology74219221. (doi:10.1016/S0301-2115(97)00091-2)

    • Search Google Scholar
    • Export Citation
  • LehmanMNCoolenLMGoodmanRL2010Minireview: Kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology15134793489. (doi:10.1210/en.2010-0022)

    • Search Google Scholar
    • Export Citation
  • LerantAFreemanME1998Ovarian steroids differentially regulate the expression of prolactin receptors in neuroendocrine dopaminergic neuron populations – a double-label confocal microscopic study. Brain Research802141154. (doi:10.1016/S0006-8993(98)00583-6)

    • Search Google Scholar
    • Export Citation
  • LiCChenPSmithMS1999Neuropeptide Y and tuberoinfundibular dopamine activities are altered during lactation: role of prolactin. Endocrinology140118123. (doi:10.1210/endo.140.1.6437)

    • Search Google Scholar
    • Export Citation
  • LiXFKinsey-JonesJSChengYKnoxAMLinYPetrouNARoseweirALightmanSLMilliganSRMillarRP2009Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS ONE4e8334. (doi:10.1371/journal.pone.0008334)

    • Search Google Scholar
    • Export Citation
  • LiQRaoAPereiraAClarkeIJSmithJT2011Kisspeptin cells in the ovine arcuate nucleus express prolactin receptor but not melatonin receptor. Journal of Neuroendocrinology23871882. (doi:10.1111/j.1365-2826.2011.02195.x)

    • Search Google Scholar
    • Export Citation
  • LiebermanMEMaurerRAClaudePWiklundJWertzNGorskiJ1981Regulation of pituitary growth and prolactin gene expression by estrogen. Advances in Experimental Medicine and Biology138151163.

    • Search Google Scholar
    • Export Citation
  • LincolnGAAnderssonHHazleriggD2003Clock genes and the long-term regulation of prolactin secretion: evidence for a photoperiod/circannual timer in the pars tuberalis. Journal of Neuroendocrinology15390397. (doi:10.1046/j.1365-2826.2003.00990.x)

    • Search Google Scholar
    • Export Citation
  • LiuBArbogastLA2008Phosphorylation state of tyrosine hydroxylase in the stalk-median eminence is decreased by progesterone in cycling female rats. Endocrinology14914621469. (doi:10.1210/en.2007-1345)

    • Search Google Scholar
    • Export Citation
  • LiuBArbogastLA2010Progesterone decreases tyrosine hydroxylase phosphorylation state and increases protein phosphatase 2A activity in the stalk-median eminence on proestrous afternoon. Journal of Endocrinology204209219. (doi:10.1677/JOE-09-0335)

    • Search Google Scholar
    • Export Citation
  • LiuXLeeKHerbisonAE2008Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels. Endocrinology14946054614. (doi:10.1210/en.2008-0321)

    • Search Google Scholar
    • Export Citation
  • LiuXBrownRSHerbisonAEGrattanDR2014Lactational anovulation in mice results from a selective loss of kisspeptin input to GnRH neurons. Endocrinology155193203. (doi:10.1210/en.2013-1621)

    • Search Google Scholar
    • Export Citation
  • LledoPMLegendrePIsraelJMVincentJD1990Dopamine inhibits two characterized voltage-dependent calcium currents in identified rat lactotroph cells. Endocrinology1279901001. (doi:10.1210/endo-127-3-990)

    • Search Google Scholar
    • Export Citation
  • LoginISMacLeodRM1977Prolactin in human and rat serum and cerebrospinal fluid. Brain Research132477483. (doi:10.1016/0006-8993(77)90196-2)

    • Search Google Scholar
    • Export Citation
  • LonsteinJSBlausteinJD2004Immunocytochemical investigation of nuclear progestin receptor expression within dopaminergic neurones of the female rat brain. Journal of Neuroendocrinology16534543. (doi:10.1111/j.1365-2826.2004.01198.x)

    • Search Google Scholar
    • Export Citation
  • LonsteinJS2007Regulation of anxiety during the postpartum period. Frontiers in Neuroendocrinology28115141.

  • LookinglandKJJarryHDMooreKE1987The metabolism of dopamine in the median eminence reflects the activity of tuberoinfundibular neurons. Brain Research419303310. (doi:10.1016/0006-8993(87)90597-X)

    • Search Google Scholar
    • Export Citation
  • LucasBKOrmandyCJBinartNBridgesRSKellyPA1998Null mutation of the prolactin receptor gene produces a defect in maternal behavior. Endocrinology13941024107. (doi:10.1210/endo.139.10.6243)

    • Search Google Scholar
    • Export Citation
  • LyonsDJHorjales-AraujoEBrobergerC2010Synchronized network oscillations in rat tuberoinfundibular dopamine neurons: switch to tonic discharge by thyrotropin-releasing hormone. Neuron65217229. (doi:10.1016/j.neuron.2009.12.024)

    • Search Google Scholar
    • Export Citation
  • LyonsDJHellysazABrobergerC2012Prolactin regulates tuberoinfundibular dopamine neuron discharge pattern: novel feedback control mechanisms in the lactotrophic axis. Journal of Neuroscience3280748083. (doi:10.1523/JNEUROSCI.0129-12.2012)

    • Search Google Scholar
    • Export Citation
  • MaFYGrattanDRGoffinVBunnSJ2005Prolactin-regulated tyrosine hydroxylase activity and messenger ribonucleic acid expression in mediobasal hypothalamic cultures: the differential role of specific protein kinases. Endocrinology14693102. (doi:10.1210/en.2004-0800)

    • Search Google Scholar
    • Export Citation
  • MacLeodRMFonthamEHLehmeyerJE1970Prolactin and growth hormone production as influenced by catecholamines and agents that affect brain catecholamines. Neuroendocrinology6283294. (doi:10.1159/000121933)

    • Search Google Scholar
    • Export Citation
  • MakGKWeissS2010Paternal recognition of adult offspring mediated by newly generated CNS neurons. Nature Neuroscience13753758. (doi:10.1038/nn.2550)

    • Search Google Scholar
    • Export Citation
  • MansourAMeador-WoodruffJHBunzowJRCivelliOAkilHWatsonSJ1990Localization of dopamine D2 receptor mRNA and D1 and D2 receptor binding in the rat brain and pituitary: an in situ hybridization-receptor autoradiographic analysis. Journal of Neuroscience1025872600.

    • Search Google Scholar
    • Export Citation
  • Martinez de la EscaleraGWeinerRI1992Dissociation of dopamine from its receptor as a signal in the pleiotropic hypothalamic regulation of prolactin secretion. Endocrine Reviews13241255. (doi:10.1210/edrv-13-2-241)

    • Search Google Scholar
    • Export Citation
  • MatsumotoMHidakaKTadaSTasakiYYamaguchiT1995Full-length cDNA cloning and distribution of human dopamine D4 receptor. Brain Research. Molecular Brain Research29157162. (doi:10.1016/0169-328X(94)00245-A)

    • Search Google Scholar
    • Export Citation
  • MatsuzakiTAzumaKIraharaMYasuiTAonoT1994Mechanism of anovulation in hyperprolactinemic amenorrhea determined by pulsatile gonadotropin-releasing hormone injection combined with human chorionic gonadotropin. Fertility and Sterility6211431149.

    • Search Google Scholar
    • Export Citation
  • MaurerRA1982Estradiol regulates the transcription of the prolactin gene. Journal of Biological Chemistry25721332136.

  • McNeilly AS 1994 Suckling and the control of gonadotropin secretion. In The Physiology of Reproduction 2nd edn pp 1179–1212. Eds E Knobil & JD Neill. New York: Raven Press.

  • McNeillyAS2001aLactational control of reproduction. Reproduction Fertility and Development13583590. (doi:10.1071/RD01056)

  • McNeillyAS2001bNeuroendocrine changes and fertility in breast-feeding women. Progress in Brain Research133207214.

  • MerchenthalerI1993Induction of enkephalin in tuberoinfundibular dopaminergic neurons during lactation. Endocrinology13326452651. (doi:10.1210/endo.133.6.7694844)

    • Search Google Scholar
    • Export Citation
  • MerchenthalerI1994Induction of enkephalin in tuberoinfundibular dopaminergic neurons of pregnant, pseudopregnant, lactating and aged female rats. Neuroendocrinology60185193. (doi:10.1159/000126750)

    • Search Google Scholar
    • Export Citation
  • MeyreDDelplanqueJChevreJCLecoeurCLobbensSGallinaSDurandEVatinVDegraeveFProencaC2009Genome-wide association study for early-onset and morbid adult obesity identifies three new risk loci in European populations. Nature Genetics41157159. (doi:10.1038/ng.301)

    • Search Google Scholar
    • Export Citation
  • MoldrupAPetersenEDNielsenJH1993Effects of sex and pregnancy hormones on growth hormone and prolactin receptor gene expression in insulin-producing cells. Endocrinology13311651172. (doi:10.1210/endo.133.3.8365359)

    • Search Google Scholar
    • Export Citation
  • MooreBJGerardo-GettensTHorwitzBASternJS1986Hyperprolactinemia stimulates food intake in the female rat. Brain Research Bulletin17563569. (doi:10.1016/0361-9230(86)90226-1)

    • Search Google Scholar
    • Export Citation
  • MorelGOuhtitAKellyPA1994Prolactin receptor immunoreactivity in rat anterior pituitary. Neuroendocrinology597884. (doi:10.1159/000126641)

    • Search Google Scholar
    • Export Citation
  • MorelGRCaronRWConsoleGMSoajeMSosaYERodriguezSSJahnGAGoyaRG2009Estrogen inhibits tuberoinfundibular dopaminergic neurons but does not cause irreversible damage. Brain Research Bulletin80347352. (doi:10.1016/j.brainresbull.2009.08.026)

    • Search Google Scholar
    • Export Citation
  • MorrellJIRosenthalMFMcCabeJTHarringtonCAChikaraishiDMPfaffDW1989Tyrosine hydroxylase mRNA in the neurons of the tuberoinfundibular region and zona incerta examined after gonadal steroid hormone treatment. Molecular Endocrinology314261433. (doi:10.1210/mend-3-9-1426)

    • Search Google Scholar
    • Export Citation
  • MoultPJReesLHBesserGM1982Pulsatile gonadotrophin secretion in hyperprolactinaemic amenorrhoea an the response to bromocriptine therapy. Clinical Endocrinology16153162. (doi:10.1111/j.1365-2265.1982.tb03159.x)

    • Search Google Scholar
    • Export Citation
  • MuraiIBen-JonathanN1987Posterior pituitary lobectomy abolishes the suckling-induced rise in prolactin (PRL): evidence for a PRL-releasing factor in the posterior pituitary. Endocrinology121205211. (doi:10.1210/endo-121-1-205)

    • Search Google Scholar
    • Export Citation
  • MuraiIBen-JonathanN1990Acute stimulation of prolactin release by estradiol: mediation by the posterior pituitary. Endocrinology12631793184. (doi:10.1210/endo-126-6-3179)

    • Search Google Scholar
    • Export Citation
  • MuraiIReichlinSBen-JonathanN1989The peak phase of the proestrous prolactin surge is blocked by either pituitary lobectomy or antisera to vasoactive intestinal peptide. Endocrinology12410501055. (doi:10.1210/endo-124-2-1050)

    • Search Google Scholar
    • Export Citation
  • NaefLWoodsideB2007Prolactin/leptin interactions in the control of food intake in rats. Endocrinology14859775983. (doi:10.1210/en.2007-0442)

    • Search Google Scholar
    • Export Citation
  • NahiFArbogastLA2003Prolactin modulates hypothalamic preproenkephalin, but not proopiomelanocortin, gene expression during lactation. Endocrine20115122. (doi:10.1385/ENDO:20:1-2:115)

    • Search Google Scholar
    • Export Citation
  • NavarroVMCastellanoJMMcConkeySMPinedaRRuiz-PinoFPinillaLCliftonDKTena-SempereMSteinerRA2011Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. American Journal of Physiology. Endocrinology and Metabolism300E202E210. (doi:10.1152/ajpendo.00517.2010)

    • Search Google Scholar
    • Export Citation
  • NewbernDFreemarkM2011Placental hormones and the control of maternal metabolism and fetal growth. Current Opinion in Endocrinology Diabetes and Obesity18409416. (doi:10.1097/MED.0b013e32834c800d)

    • Search Google Scholar
    • Export Citation
  • NicholsonGGreeleyGHJrHummJYoungbloodWWKizerJS1980Prolactin in cerebrospinal fluid: a probable site of prolactin autoregulation. Brain Research190447457. (doi:10.1016/0006-8993(80)90287-5)

    • Search Google Scholar
    • Export Citation
  • Nikitovitch-WinerMEverettJW1958Functional restitution of pituitary grafts re-transplanted from kidney to median eminence. Endocrinology63916930. (doi:10.1210/endo-63-6-916)

    • Search Google Scholar
    • Export Citation
  • NilssonLOlssonAHIsomaaBGroopLBilligHLingC2011A common variant near the PRL gene is associated with increased adiposity in males. Molecular Genetics and Metabolism1027881. (doi:10.1016/j.ymgme.2010.08.017)

    • Search Google Scholar
    • Export Citation
  • NoelMBWoodsideB1993Effects of systemic and central prolactin injections on food intake, weight gain, and estrous cyclicity in female rats. Physiology & Behavior54151154. (doi:10.1016/0031-9384(93)90057-M)

    • Search Google Scholar
    • Export Citation
  • NolanLALevyA2009The trophic effects of oestrogen on male rat anterior pituitary lactotrophs. Journal of Neuroendocrinology21457464. (doi:10.1111/j.1365-2826.2009.01864.x)

    • Search Google Scholar
    • Export Citation
  • OakleyAECliftonDKSteinerRA2009Kisspeptin signaling in the brain. Endocrine Reviews30713743. (doi:10.1210/er.2009-0005)

  • OrmandyCJBinartNKellyPA1997Mammary gland development in prolactin receptor knockout mice. Journal of Mammary Gland Biology and Neoplasia2355364. (doi:10.1023/A:1026395229025)

    • Search Google Scholar
    • Export Citation
  • ParkSKSelmanoffM1991Dose-dependent suppression of postcastration luteinizing hormone secretion exerted by exogenous prolactin administration in male rats: a model for studying hyperprolactinemic hypogonadism. Neuroendocrinology53404410. (doi:10.1159/000125748)

    • Search Google Scholar
    • Export Citation
  • ParkSKKeenanMWSelmanoffM1993Graded hyperprolactinemia first suppresses LH pulse frequency and then pulse amplitude in castrated male rats. Neuroendocrinology58448453. (doi:10.1159/000126575)

    • Search Google Scholar
    • Export Citation
  • ParkerSLArmstrongWESladekCDGrosvenorCECrowleyWR1991Prolactin stimulates the release of oxytocin in lactating rats: evidence for a physiological role via an action at the neural lobe. Neuroendocrinology53503510.

    • Search Google Scholar
    • Export Citation
  • ParsonsJABreljeTCSorensonRL1992Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology13014591466. (doi:10.1210/endo.130.3.1537300)

    • Search Google Scholar
    • Export Citation
  • PasqualiniCGuibertBLevielV1993Short-term inhibitory effect of estradiol on tyrosine hydroxylase activity in tuberoinfundibular dopaminergic neurons in vitro. Journal of Neurochemistry6017071713. (doi:10.1111/j.1471-4159.1993.tb13394.x)

    • Search Google Scholar
    • Export Citation
  • PasteelsJL1963Morphological and experimental research on prolactin secretion. Archives de Biologie74439553.

  • PatelSSBamigboyeV2007Hyperprolactinaemia. Journal of Obstetrics and Gynaecology27455459. (doi:10.1080/01443610701406125)

  • PetersLLHoeferMTBen-JonathanN1981The posterior pituitary: regulation of anterior pituitary prolactin secretion. Science213659661. (doi:10.1126/science.7256264)

    • Search Google Scholar
    • Export Citation
  • PetrykAFleenorDDriscollPFreemarkM2000Prolactin induction of insulin gene expression: the roles of glucose and glucose transporter-2. Journal of Endocrinology164277286. (doi:10.1677/joe.0.1640277)

    • Search Google Scholar
    • Export Citation
  • PiXJGrattanDR1998aDifferential expression of the two forms of prolactin receptor mRNA within microdissected hypothalamic nuclei of the rat. Brain Research. Molecular Brain Research59112. (doi:10.1016/S0169-328X(98)00109-0)

    • Search Google Scholar
    • Export Citation
  • PiXJGrattanDR1998bDistribution of prolactin receptor immunoreactivity in the brain of estrogen-treated, ovariectomized rats. Journal of Comparative Neurology394462474. (doi:10.1002/(SICI)1096-9861(19980518)394:4<462::AID-CNE5>3.0.CO;2-#)

    • Search Google Scholar
    • Export Citation
  • PinillaLAguilarEDieguezCMillarRPTena-SempereM2012Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiological Reviews9212351316. (doi:10.1152/physrev.00037.2010)

    • Search Google Scholar
    • Export Citation
  • van den PolANHerbstRSPowellJF1984Tyrosine hydroxylase-immunoreactive neurons of the hypothalamus: a light and electron microscopic study. Neuroscience1311171156. (doi:10.1016/0306-4522(84)90292-6)

    • Search Google Scholar
    • Export Citation
  • PolsonDWSagleMMasonHDAdamsJJacobsHSFranksS1986Ovulation and normal luteal function during LHRH treatment of women with hyperprolactinaemic amenorrhoea. Clinical Endocrinology24531537. (doi:10.1111/j.1365-2265.1986.tb03282.x)

    • Search Google Scholar
    • Export Citation
  • Ramos-RomanMA2011Prolactin and lactation as modifiers of diabetes risk in gestational diabetes. Hormone and Metabolic Research43593600. (doi:10.1055/s-0031-1284353)

    • Search Google Scholar
    • Export Citation
  • RaymondVBeaulieuMLabrieFBoissierJ1978Potent antidopaminergic activity of estradiol at the pituitary level on prolactin release. Science20011731175. (doi:10.1126/science.418505)

    • Search Google Scholar
    • Export Citation
  • RieckSKaestnerKH2010Expansion of β-cell mass in response to pregnancy. Trends in Endocrinology and Metabolism21151158. (doi:10.1016/j.tem.2009.11.001)

    • Search Google Scholar
    • Export Citation
  • RomanoNYipSHHodsonDJGuillouAParnaudeauSKirkSTroncheFBonnefontXLe TissierPBunnSJ2013Plasticity of hypothalamic dopamine neurons during lactation results in dissociation of electrical activity and release. Journal of Neuroscience3344244433. (doi:10.1523/JNEUROSCI.4415-12.2013)

    • Search Google Scholar
    • Export Citation
  • RosenblattJS1967Nonhormonal basis of maternal behavior in the rat. Science15615121514. (doi:10.1126/science.156.3781.1512)

  • RoseweirAKKauffmanASSmithJTGuerrieroKAMorganKPielecka-FortunaJPinedaRGottschMLTena-SempereMMoenterSM2009Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. Journal of Neuroscience2939203929. (doi:10.1523/JNEUROSCI.5740-08.2009)

    • Search Google Scholar
    • Export Citation
  • de RouxNGeninECarelJCMatsudaFChaussainJLMilgromE2003Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. PNAS1001097210976. (doi:10.1073/pnas.1834399100)

    • Search Google Scholar
    • Export Citation
  • SaiardiABozziYBaikJHBorrelliE1997Antiproliferative role of dopamine: loss of D2 receptors causes hormonal dysfunction and pituitary hyperplasia. Neuron19115126. (doi:10.1016/S0896-6273(00)80352-9)

    • Search Google Scholar
    • Export Citation
  • SakaguchiKTanakaMOhkuboTDohuraKFujikawaTSudoSNakashimaK1996Induction of brain prolactin receptor long-form mRNA expression and maternal behavior in pup-contacted male rats: promotion by prolactin administration and suppression by female contact. Neuroendocrinology63559568. (doi:10.1159/000127085)

    • Search Google Scholar
    • Export Citation
  • SamsonWKMartinLMoggRJFultonRJ1990A nonoxytocinergic prolactin releasing factor and a nondopaminergic prolactin inhibiting factor in bovine neurointermediate lobe extracts: in vitro and in vivo studies. Endocrinology12616101617. (doi:10.1210/endo-126-3-1610)

    • Search Google Scholar
    • Export Citation
  • SapsfordTJKokayICOstbergLBridgesRSGrattanDR2011Differential sensitivity of specific neuronal populations of the rat hypothalamus to prolactin action. Journal of Comparative Neurology52010621077.(doi:10.1002/cne.22775)

    • Search Google Scholar
    • Export Citation
  • SapsfordTJKokayICOstbergLBridgesRSGrattanDR2012Differential sensitivity of specific neuronal populations of the rat hypothalamus to prolactin action. Journal of Comparative Neurology52010621077. (doi:10.1002/cne.22775)

    • Search Google Scholar
    • Export Citation
  • SarM1984Estradiol is concentrated in tyrosine hydroxylase-containing neurons of the hypothalamus. Science223938940. (doi:10.1126/science.6141639)

    • Search Google Scholar
    • Export Citation
  • SarM1988Distribution of progestin-concentrating cells in rat brain: colocalization of [3H]ORG.2058, a synthetic progestin, and antibodies to tyrosine hydroxylase in hypothalamus by combined autoradiography and immunocytochemistry. Endocrinology12311101118. (doi:10.1210/endo-123-2-1110)

    • Search Google Scholar
    • Export Citation
  • SarkarDKFrautschySAMitsugiN1992Pituitary portal plasma levels of oxytocin during the estrous cycle, lactation, and hyperprolactinemia. Annals of the New York Academy of Sciences652397410. (doi:10.1111/j.1749-6632.1992.tb34370.x)

    • Search Google Scholar
    • Export Citation
  • SauvéDWoodsideB1996The effect of central administration of prolactin on food intake in virgin female rats is dose-dependent, occurs in the absence of ovarian hormones and the latency to onset varies with feeding regimen. Brain Research7297581. (doi:10.1016/0006-8993(96)00227-2)

    • Search Google Scholar
    • Export Citation
  • SauvéDWoodsideB2000Neuroanatomical specificity of prolactin-induced hyperphagia in virgin female rats. Brain Research868306314. (doi:10.1016/S0006-8993(00)02344-1)

    • Search Google Scholar
    • Export Citation
  • SchaefferMLangletFLafontCMolinoFHodsonDJRouxTLamarqueLVerdiePBourrierEDehouckB2013Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. PNAS11015121517. (doi:10.1073/pnas.1212137110)

    • Search Google Scholar
    • Export Citation
  • SchradinC2007Comments to K.E. Wynne-Edwards and M.E. Timonin 2007. Paternal care in rodents: weakening support of hormonal regulation of the transition to behavioral fatherhood in rodent animal models of biparental care, Horm & Behav 52: 114-121. Hormones and Behavior52557559.reply 560 (doi:10.1016/j.yhbeh.2007.08.008)

    • Search Google Scholar
    • Export Citation
  • SchradinCAnzenbergerG1999Prolactin, the hormone of paternity. News in Physiological Sciences14223231.

  • SchraenenALemaireKde FaudeurGHendrickxNGranvikMVan LommelLMalletJVodjdaniGGilonPBinartN2010Placental lactogens induce serotonin biosynthesis in a subset of mouse β cells during pregnancy. Diabetologia5325892599. (doi:10.1007/s00125-010-1913-7)

    • Search Google Scholar
    • Export Citation
  • ScullyKMGleibermanASLindzeyJLubahnDBKorachKSRosenfeldMG1997Role of estrogen receptor-α in the anterior pituitary gland. Molecular Endocrinology11674681. (doi:10.1210/mend.11.6.0019)

    • Search Google Scholar
    • Export Citation
  • SelmanoffM1985Rapid effects of hyperprolactinemia on basal prolactin secretion and dopamine turnover in the medial and lateral median eminence. Endocrinology11619431952. (doi:10.1210/endo-116-5-1943)

    • Search Google Scholar
    • Export Citation
  • SelmanoffMGregersonKA1985Suckling decreases dopamine turnover in both medial and lateral aspects of the median eminence in the rat. Neuroscience Letters572530. (doi:10.1016/0304-3940(85)90035-7)

    • Search Google Scholar
    • Export Citation
  • SelmanoffMWisePM1981Decreased dopamine turnover in the median eminence in response to suckling in the lactating rat. Brain Research212101115. (doi:10.1016/0006-8993(81)90036-6)

    • Search Google Scholar
    • Export Citation
  • SelmanoffMShuCPetersenSLBarracloughCAZoellerRT1991Single cell levels of hypothalamic messenger ribonucleic acid encoding luteinizing hormone-releasing hormone in intact, castrated, and hyperprolactinemic male rats. Endocrinology128459466. (doi:10.1210/endo-128-1-459)

    • Search Google Scholar
    • Export Citation
  • SeminaraSBMessagerSChatzidakiEEThresherRRAciernoJSJrShagouryJKBo-AbbasYKuohungWSchwinofKMHendrickAG2003The GPR54 gene as a regulator of puberty. New England Journal of Medicine34916141627. (doi:10.1056/NEJMoa035322)

    • Search Google Scholar
    • Export Citation
  • ShanksNWindleRJPerksPWoodSIngramCDLightmanSL1999The hypothalamic–pituitary–adrenal axis response to endotoxin is attenuated during lactation. Journal of Neuroendocrinology11857865.erratum 12 471

    • Search Google Scholar
    • Export Citation
  • ShingoTGreggCEnwereEFujikawaHHassamRGearyCCrossJCWeissS2003Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science299117120. (doi:10.1126/science.1076647)

    • Search Google Scholar
    • Export Citation
  • ShirleyB1984The food intake of rats during pregnancy and lactation. Laboratory Animal Science34169172.

  • ShortRV1976Lactation – the central control of reproduction. Ciba Foundation Symposium457386.

  • SinhaYNSorensonRL1993Differential effects of glycosylated and nonglycosylated prolactin on islet cell division and insulin secretion. Proceedings of the Society for Experimental Biology and Medicine203123126. (doi:10.3181/00379727-203-43582aa)

    • Search Google Scholar
    • Export Citation
  • SlatteryDANeumannID2008No stress please! Mechanisms of stress hyporesponsiveness of the maternal brain. Journal of Physiology586377385.

    • Search Google Scholar
    • Export Citation
  • SmithMS1978A comparison of pituitary responsiveness to luteinizing hormone-releasing hormone during lactation and the estrous cycle of the rat. Endocrinology102114120. (doi:10.1210/endo-102-1-114)

    • Search Google Scholar
    • Export Citation
  • SmithMS1982Effect of pulsatile gonadotropin-releasing hormone on the release of luteinizing hormone and follicle-stimulating hormone in vitro by anterior pituitaries from lactating and cycling rats. Endocrinology110882891. (doi:10.1210/endo-110-3-882)

    • Search Google Scholar
    • Export Citation
  • SmithMSTrueCGroveKL2010The neuroendocrine basis of lactation-induced suppression of GnRH: role of kisspeptin and leptin. Brain Research1364139152. (doi:10.1016/j.brainres.2010.08.038)

    • Search Google Scholar
    • Export Citation
  • SonigoCBouillyJCarreNTolleVCaratyATelloJSimony-ConesaFJMillarRYoungJBinartN2012Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration. Journal of Clinical Investigation12237913795. (doi:10.1172/JCI63937)

    • Search Google Scholar
    • Export Citation
  • SorensonRLParsonsJA1985Insulin secretion in mammosomatotropic tumor-bearing and pregnant rats. A role for lactogens. Diabetes34337341. (doi:10.2337/diab.34.4.337)

    • Search Google Scholar
    • Export Citation
  • SorensonRLStoutLE1995Prolactin receptors and JAK2 in islets of Langerhans: an immunohistochemical analysis. Endocrinology13640924098. (doi:10.1210/endo.136.9.7649117)

    • Search Google Scholar
    • Export Citation
  • SteynFJAndersonGMGrattanDR2007Expression of ovarian steroid hormone receptors in tuberoinfundibular dopaminergic neurones during pregnancy and lactation. Journal of Neuroendocrinology19788793. (doi:10.1111/j.1365-2826.2007.01590.x)

    • Search Google Scholar
    • Export Citation
  • SteynFJAndersonGMGrattanDR2008Hormonal regulation of suppressors of cytokine signaling (SOCS) messenger ribonucleic acid in the arcuate nucleus during late pregnancy. Endocrinology14932063214. (doi:10.1210/en.2007-1623)

    • Search Google Scholar
    • Export Citation
  • SzaboFKLeWWSnyderNSHoffmanGE2011Comparison of the temporal programs regulating tyrosine hydroxylase and enkephalin expressions in TIDA neurons of lactating rats following pup removal and then pup return. Journal of Molecular Neuroscience45110118. (doi:10.1007/s12031-010-9466-2)

    • Search Google Scholar
    • Export Citation
  • TakahashiSOkazakiKKawashimaS1984Mitotic activity of prolactin cells in the pituitary glands of male and female rats of different ages. Cell and Tissue Research235497502. (doi:10.1007/BF00226945)

    • Search Google Scholar
    • Export Citation
  • TalwalkerPKRatnerAMeitesJ1963In vitro inhibition of pituitary prolactin synthesis and release by hypothalamic extract. American Journal of Physiology205213218.

    • Search Google Scholar
    • Export Citation
  • TornerLNeumannID2002The brain prolactin system: involvement in stress response adaptations in lactation. Stress5249257.

  • TornerLToschiNPohlingerALandgrafRNeumannID2001Anxiolytic and anti-stress effects of brain prolactin: improved efficacy of antisense targeting of the prolactin receptor by molecular modeling. Journal of Neuroscience2132073214.

    • Search Google Scholar
    • Export Citation
  • TortoneseDJBrooksJIngletonPMMcNeillyAS1998Detection of prolactin receptor gene expression in the sheep pituitary gland and visualization of the specific translation of the signal in gonadotrophs. Endocrinology13952155223. (doi:10.1210/endo.139.12.6365)

    • Search Google Scholar
    • Export Citation
  • TrottJFSchenninkAPetrieWKManjarinRVanKlompenbergMKHoveyRC2012Triennial Lactation Symposium: Prolactin: the multifaceted potentiator of mammary growth and function. Journal of Animal Science9016741686. (doi:10.2527/jas.2011-4682)

    • Search Google Scholar
    • Export Citation
  • TrueCKirigitiMCiofiPGroveKLSmithMS2011Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat. Journal of Neuroendocrinology235264. (doi:10.1111/j.1365-2826.2010.02076.x)

    • Search Google Scholar
    • Export Citation
  • TsukamuraHMaedaK2001Non-metabolic and metabolic factors causing lactational anestrus: rat models uncovering the neuroendocrine mechanism underlying the suckling-induced changes in the mother. Progress in Brain Research133187205.

    • Search Google Scholar
    • Export Citation
  • ValeggiaCEllisonPT2009Interactions between metabolic and reproductive functions in the resumption of postpartum fecundity. American Journal of Human Biology21559566. (doi:10.1002/ajhb.20907)

    • Search Google Scholar
    • Export Citation
  • ValerioAAlbericiATintiCSpanoPMemoM1994Antisense strategy unravels a dopamine receptor distinct from the D2 subtype, uncoupled with adenylyl cyclase, inhibiting prolactin release from rat pituitary cells. Journal of Neurochemistry6212601266. (doi:10.1046/j.1471-4159.1994.62041260.x)

    • Search Google Scholar
    • Export Citation
  • WalshRJPosnerBIKopriwaBMBrawerJR1978Prolactin binding sites in the rat brain. Science20110411043. (doi:10.1126/science.684427)

  • WalshRJSlabyFJPosnerBI1987