News Physiol Sci 14: 54-58, 1999;
1548-9213/99 $5.00
News in Physiological Sciences, Vol. 14, No. 2, 54-58,
April 1999
© 1999 Int. Union Physiol. Sci./Am. Physiol. Soc.
Toward Multifactorial Hypothalamic Regulation of Anterior Pituitary Hormone Secretion
W. R. Crowley
W. R. Crowley is Professor, Department of Pharmacology, University of Tennessee, Memphis College of Medicine, Memphis TN 38163, USA.
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Abstract
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The hypothalamus regulates the secretion of anterior pituitary hormones via release of releasing hormones into the hypophysial portal vasculature. Additional neuromessengers act at the pituitary to modulate responses to the hypothalamic hormones. For example, neuropeptide Y enhances the effect of gonadotropin-releasing hormone and the response to the prolactin-inhibiting hormone dopamine.
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Introduction
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Over the last two decades, a number of neuromessengers, including classical as well as peptidergic neurotransmitters, have been implicated in the regulation of anterior and posterior pituitary hormone secretion. One can conceptualize these neurochemical systems as transducers of physiological signals from the external environment (e.g., the nursing stimulation provided by the suckling offspring) and from the internal milieu (e.g., ovarian hormone feedback) into relevant pituitary hormonal secretory events [e.g., prolactin (PRL) secretion during lactation and the preovulatory luteinizing hormone (LH) surge, respectively], which in turn regulate the critical physiological processes of ovulation and lactation.
Fig. 1
(top) schematizes the traditional view of the regulation of anterior pituitary (AP) protein hormone secretion by the brain, particularly the hypothalamus. That the brain communicates to the AP via a neurovascular link, the hypothalamo-hypophysial portal system, rather than through direct neural connections, has been recognized for decades. Clusters of neurosecretory cells within the hypothalamus and basal forebrain synthesize a variety of hypothalamic hormones, which are secreted into this vasculature and which signal release or inhibition of release of their cognate AP hormone. In this classical scheme, the neurosecretion of the hypothalamic releasing and inhibiting hormones has been viewed as the ultimate step in the neural regulation of AP secretion. That is, each of these neurosecretory systems has been viewed as integrating the various external and internal influences relevant to the secretion of an AP hormone and then conveying a unified signal to the relevant AP cells.
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FIGURE 1. Traditional vs. emerging views of the hypothalamic regulation of anterior pituitary (AP) hormone secretion. In the classical view (top), hypothalamic releasing hormones (RHs) are innervated by and integrate signals from various brain neurotransmitters (NTs) and neuropeptides (NPs) that govern the neurosecretion of the RHs, which provide a unified signal to specific AP cell types. In the emerging view (bottom), some neuromessengers, in addition to regulating release of the RHs, also act at the level of the AP to modulate the response to the RH.
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In recent years, however, evidence has accumulated to challenge the view that the well-recognized releasing and inhibiting hormones comprise the only signals from the brain to the AP. It is now clear that in addition to the classical releasing hormones, other active factors are secreted into the hypophysial portal blood and exert important actions at the level of the AP to modulate the responses of AP cells to their specific hypothalamic hormones (Fig. 1
, bottom). This emerging concept, therefore, views the hypothalamic control of AP secretion as pleiotropic or multifactorial, in that multiple signals deriving from the brain interact at the level of the AP gland to influence protein hormone secretion.
To illustrate such multiple hypothalamic signaling to the AP, this article reviews findings obtained by this laboratory on the actions of neuropeptide Y (NPY), an abundant brain peptide, in two physiological contexts, the preovulatory LH surge and PRL secretion during lactation. In each of these instances, NPY is released into the pituitary portal vasculature and acts at the AP to amplify the signals provided by the major hypothalamic hormone.
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NPY and LH secretion: interaction with gonadotropin-releasing hormone
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In small mammals such as rats, LH is secreted at low levels, albeit in a pulsatile manner, throughout most of the estrous cycle, except for the afternoon of the day of proestrus, at which time there is a massive discharge of the hormone, which is responsible for the rupture of the ovarian follicles and release of the ova later that night (cf. Ref. 7 for review). It is well established that the preovulatory LH surge is stimulated by "positive feedback" actions of the ovarian hormones estradiol and progesterone, which act in concert to stimulate the neurosecretion of gonadotropin-releasing hormone (GnRH), the major stimulatory releasing factor for the gonadotropins, from the hypothalamus into the pituitary portal vasculature (7). In all likelihood, however, ovarian hormones do not act directly at the level of the GnRH neurons, because these cells lack nuclear steroid receptors (13). Rather, attention has been focused on a number of other neurochemical systems (Fig. 2) as the major targets for ovarian hormone stimulatory feedback. Even though the precise neurochemical mechanisms remain to be elucidated, it now seems clear that ovarian hormones affect GnRH secretion indirectly, i.e., by modifying the level of activity of these, and undoubtedly other, excitatory and inhibitory neurochemical inputs to the GnRH neurons.
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FIGURE 2. Neuroendocrine regulation of luteinizing hormone (LH) secretion. Excitatory influences over the secretion of LH-releasing hormone (LHRH) include glutamate (GLU), norepinephrine (NE), and neuropeptide Y (NPY), whereas inhibitory influences include  -aminobutyric acid (GABA) and endogenous opioid peptides (EOP), particularly ß-endorphin.
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Considerable evidence implicates NPY as a neuromessenger that participates in the mechanisms underlying ovarian hormone positive feedback on LH. NPY is a 36-amino acid peptide of the pancreatic polypeptide family, initially characterized as the peptidergic cotransmitter with norepinephrine (NE) in the sympathetic nervous system; NPY is also coexpressed with NE and epinephrine in many of the central adrenergic neurons, but its distribution in brain is not limited to these systems (cf. Ref. 6 for review). Indeed, NPY is the most widely distributed neuropeptide, with nonadrenergic cell groups in many brain areas, including cortex, striatum, and hypothalamus.
In the sympathetic nervous system, NPY generally exerts direct actions similar to NE and enhances the postjunctional responses to NE; these actions are particularly marked in cardiovascular tissues (6). Our studies also reveal similarities and interactions between NE and NPY in the control of LH secretion. As summarized previously (4, 6), when administered centrally NPY stimulates LH release and enhances NE-induced LH release; these effects require appropriate ovarian hormone exposure. As for NE, one site of NPY action is the median eminence, site of the GnRH-secreting nerve terminals; we envision that NPY evokes GnRH release through a nonclassical, terminal-to-terminal mode of neuronal communication. Our studies on signal transduction indicate that NE, acting via an 
1 type of adrenergic receptor, and NPY, acting via the Y-1 subtype of NPY receptor, act in concert postjunctionally to produce an additive mobilization of intracellular Ca2+, which then promotes exocytosis of the hypothalamic hormone (reviewed in Refs. 4 and 6).
That hypothalamic NPY neurons participate in ovarian hormone positive feedback is strongly suggested by our findings that 1) a substantial proportion of arcuate NPY cells contain nuclear estradiol receptors (6); 2) in the hours preceding a spontaneous or hormone-induced LH surge, there is an abrupt increase in preproNPY gene expression and accumulation of the peptide in the median eminence nerve terminals, followed by release of the peptide (12); and 3) interference with the ovarian hormone-induced upregulation of NPY synthesis with antisense deoxy-oligonucleotides, or blockade of NPY action by immunoneutralization, blocks spontaneous or hormone-induced LH surges (4, 6, 15).
Taken together, these observations are consistent with NPY's participation in the control of preovulatory LH release in the traditional mode of neuroendocrine control, i.e., regulation of secretion of a hypothalamic hormone. Other findings, however, indicate a second site of NPY action, and a novel mode of signaling, in which NPY acts directly on the gonadotropes of the AP to augment their response to GnRH. Spurred by observations of dynamic changes in NPY concentrations in the median eminence and in portal blood, in conjunction with GnRH, we found, using cultured AP cells, that NPY, although lacking direct effects on LH secretion, nevertheless significantly enhanced GnRH-induced LH secretion from these cells (3). We further showed, through a combination of pharmacological and biochemical approaches, that NPY enhances that aspect of GnRH signal transduction involving entry of extracellular Ca2+ through L-type, voltage-dependent calcium channels (5). It seems, then, that the heightened level of cytosolic Ca2+ in the gonadotrope resulting from combined GnRH/NPY action would promote exocytosis of LH.
Further pharmacological studies indicated a remarkable specificity to NPY action on LH secretion, in that NPY failed to facilitate LH release evoked by more nonselective secretagogues, including the calcium-channel activator maitotoxin or elevated KCl depolarization. This suggested that activation of the GnRH receptor was necessary for the facilitatory action of NPY. Indeed, using a variety of ligand binding approaches, Dr. Steven Parker (11) has demonstrated that NPY increases the binding of a GnRH agonist to AP membrane receptors, and kinetically, this enhancement appears as an increase in the affinity of the ligand-receptor interaction. The precise cellular means by which NPY modulates GnRH receptor binding remain to be established, although others have suggested that it might result from an action of protein kinase C consequent to NPY receptor stimulation and activation of the Ca2+-inositol phosphate messenger cascade (9).
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NPY and PRL secretion: interaction with tuberoinfundibular dopamine
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The neuroendocrine regulation of PRL secretion is more complex than that over the gonadotropins, in that the hypothalamus releases hormones that exert both inhibitory [dopamine (DA)] and stimulatory [thyrotropin-releasing hormone (TRH) and others] actions on the secretion of this hormone (reviewed in Refs. 8 and 10; see Fig. 3). As with LH, however, recent work suggests that additional signals emerge from the brain to interact with these primary hypothalamic hormones, with one example being NPY, which also exerts a signal amplification action during lactation in the control over PRL secretion. During lactation, there is a general upregulation of hypothalamic NPY expression in the hypothalamus, including a novel expression of the peptide within the tuberoinfundibular dopamine (TIDA) neurons, which normally do not express this peptide (1, 2).
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FIGURE 3. Neuroendocrine regulation of prolactin (PRL) secretion. Excitatory influences over the secretion of PRL are mediated by endogenous opioid peptides (EOP), serotonin (5-HT), and -aminobutyric acid (GABA) via reciprocal influences on the PRL-releasing hormone thyrotropin-releasing hormone (TRH) and the PRL-inhibitory hormone dopamine (DA).
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These observations reveal a marked neurochemical plasticity in this neurosecretory system. At present, the physiological signals associated with lactation that evoke the novel expression of this peptide in TIDA cells are not known but likely involve some aspect of the afferent stimuli provided by the nursing offspring, because we found that removal of the litters for 24 h markedly reduced NPY immunostaining in the TIDA nerve endings of the median eminence (1, 14). Thus it is possible that the afferent barrage into the medial basal hypothalamus either directly or indirectly signals these cells to synthesize NPY. We tested the possibility that PRL released by nursing might be responsible, in view of the well-known activation of TIDA neurons by PRL, as part of a negative feedback loop. However, we have been unable to mimic the effect of lactation in inducing NPY expression in TIDA neurons by elevating circulating PRL in nonlactating rats via pharmacological approaches; conversely, pharmacological blockade of nursing-induced PRL secretion did not mimic the inhibitory effect of litter removal in reducing NPY expression. Rather, it seems likely that NPY expression might be directed through stimulus-transcription coupling mechanisms, involving the multisynaptic afferent barrage activated by nursing.
Because DA released from TIDA neurons is the major hypothalamic inhibitory hormone regulating PRL, we tested whether NPY might also affect PRL secretion and whether it might modulate the inhibitory action of DA on PRL secretion. Initial studies in cultured AP cells prepared from lactating rats showed that NPY mimicked DA in suppressing basal, as well as TRH-induced, PRL secretion and enhanced the inhibitory actions of DA in an additive manner (14). Thus the physiological role of NPY, when coexpressed with DA in TIDA neurons in lactation, may be to augment the inhibitory signals provided by DA to lactotropes.
Despite decades of intensive research, the precise signal transduction mechanisms affected by DA to inhibit PRL secretion remain incompletely understood (8, 10). Inhibition of extracellular Ca2+ entry, possibly via membrane hyperpolarization, is perhaps the best characterized action of DA, which acts via the D-2 subtype of receptor; however, evidence exists for other effects, including negative coupling to Ca2+/inositol phosphate signaling, inhibition of cAMP synthesis, as well as intracellular mechanisms. Pharmacological and biochemical studies in this laboratory have attempted to define the signal transduction pathways activated by NPY in the inhibition of PRL release and interaction with DA (14). Our studies suggest that NPY's inhibition of PRL secretion occurs through a receptor resembling the "Y-5" subtype, which is also thought to mediate the feeding response, and mechanisms associated with inhibition of extracellular Ca2+ entry. For example, both NPY and DA alone impair the TRH-induced rise in cytosolic Ca2+ that precedes PRL release, and the combination of DA and NPY has a more profound inhibitory effect on cytosolic Ca2+ concentration ([Ca2+ ]i), and on PRL release, than either alone. However, depletion of extracellular Ca2+ abolishes the inhibitory effect of NPY on the TRH-induced increase in [Ca2+]i and PRL release, although DA is still effective in these conditions, and also eliminates the additive interaction of NPY with DA on these measures. Moreover, NPY does not prevent either the rise in [Ca2+ ]i or PRL release induced by ionomycin, which preferentially releases Ca2+ from intracellular stores; in contrast, DA antagonizes these responses. Thus, from our studies, it appears that DA receptors are coupled to inhibition of both intracellular mobilization and entry of extracellular Ca2+, whereas NPY receptors are coupled more specifically and selectively to inhibition of the entry of extracellular Ca2+.
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Summary
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As exemplified by these signal amplification actions of NPY, it appears clear that the specific protein hormone-secreting endocrine cells of the AP must process signals not only from their cognate classical hypothalamic hormone(s), but also from additional centrally derived factors. In the case of the preovulatory LH surge, the enhancement by NPY of GnRH binding to its receptor might play an important physiological role early in the onset of the LH surge by amplifying the initial GnRH signal. In lactation, the novel expression of NPY in TIDA neurons may provide an additional inhibitory signal to the lactotropes; this could result in greater "fine-tuning" of PRL secretion in this physiological condition. Undoubtedly, additional neuroendocrine modulating factors will be identified for these and other AP systems.
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References
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Ciofi, P., W. R. Crowley, A. Pillez, L. L. Schmued, G. Tramu, and M. Mazzuca. Plasticity in expression of immunoreactivity for neuropeptide Y, enkephalins and neurotensin in the hypothalamic tubero-infundibular dopaminergic system during lactation in mice. J. Neuroendocrinol. 5: 599–602, 1993.[Medline]
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Ciofi. P., J. H. Fallon, D. Croix, J. M. Polak, and G. Tramu. Expression of neuropeptide Y precursor immunoreactivity in the hypothalamic dopaminergic tubero-infundibular system during lactation in rodents. Endocrinology 128: 823–824, 1991.[Abstract/Free Full Text]
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Crowley, W. R., A. Hassid, and S. P. Kalra. Neuropeptide Y enhances the release of luteinizing hormone (LH) induced by LH-releasing hormone. Endocrinology 120: 941–945, 1987.[Abstract/Free Full Text]
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Crowley, W. R., S. L. Parker, A. Sahu, and S. P. Kalra. Interacting transmembrane signals regulating GnRH and LH secretion. In: The Neurobiology of Puberty, edited by T. M. Plant and P. A. Lee, Bristol, UK: Blackwell Science, 1995, p. 41–54.
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Crowley, W. R., G. V. Shah, B. L. Carroll, D. Kennedy, M. D. Dockter, and S. P. Kalra. Neuropeptide Y enhances luteinizing hormone (LH)-releasing hormone-induced LH release and elevations in cytosolic Ca2+ in rat anterior pituitary cells: evidence for involvement of extracellular Ca2+ influx through voltage-sensitive channels. Endocrinology 127: 1487–1494, 1990.[Abstract/Free Full Text]
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Kalra, S. P., and W. R. Crowley. Neuropeptide Y: a novel neuroendocrine peptide in the control of pituitary hormone secretion, and its relation to luteinizing hormone. Front. Neuroendocrinol. 13: 1–46, 1992.[Medline]
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Kalra, S. P., and P. S. Kalra. Neural regulation of luteinizing hormone in the rat. Endocr. Rev. 4: 311–351, 1983.[Abstract/Free Full Text]
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Lamberts, S. W. J., and R. M. MacLeod. Regulation of prolactin secretion at the level of the lactotroph. Physiol. Rev. 70: 279–318, 1990.[Free Full Text]
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Leblanc, P., A. Lheritier, R. Rasolonjanahary, and C. A. Kordon. Neuropeptide Y enhances GnRH binding to rat gonadotrophs in primary culture. Neuropeptides 26: 87–92, 1994.[Medline]
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Martinez de la Escalera, G., and R. I. Weiner. Dissociation of dopamine from its receptor as a signal in the pleiotropic hypothalamic regulation of prolactin secretion. Endocr. Rev. 13: 241–255, 1992.[Abstract/Free Full Text]
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Parker, S. L., S. P. Kalra, and W. R. Crowley. Neuropeptide Y modulates the binding of a gonadotropin-releasing hormone (GnRH) analog to anterior pituitary GnRH receptor sites. Endocrinology 128: 2309–2316, 1991.[Abstract/Free Full Text]
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Sahu, A., W. R. Crowley, and S. P. Kalra. Hypothalamic neuropeptide-Y gene expression increases before the onset of the ovarian steroid-induced luteinizing hormone surge. Endocrinology 134: 1018–1022, 1994.[Abstract/Free Full Text]
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Shivers, B., R. Harlan, J. I. Morrell, and D.W. Pfaff. Absence of oestradiol concentration in cell nuclei of LHRH-immunoreactive neurons. Nature 304: 345–347, 1983.[Medline]
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Wang, J., P. Ciofi, and W. R. Crowley. Neuropeptide Y suppresses prolactin secretion from rat anterior pituitary cells: evidence for interactions with dopamine through inhibitory coupling to calcium entry. Endocrinology 137: 587–594, 1996.[Abstract]
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Xu. B., A. Sahu, P. S. Kalra, W. R. Crowley, and S. P. Kalra. Disinhibition from opioid influence augments hypothalamic neuropeptide Y (NPY) gene expression and pituitary luteinizing hormone release: effects of NPY messenger ribonucleic acid antisense oligodeoxynucleotides. Endocrinology 137: 78–84, 1996.[Abstract]
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Introduction
NPY and LH secretion:...
