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Department of Physiology, University of Adelaide, Adelaide, SA 5005 Australia; and Departments of Obstetrics & Gynecology and Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157
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Abstract |
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 Top Abstract I. IntroductionII. Factors That Are...III. Intrapituitary Interactions...IV. ConclusionReferences |
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-MSH -Subunit |
I. Introduction |
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TopAbstractI. IntroductionII. Factors That Are...III. Intrapituitary Interactions...IV. ConclusionReferences |
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This review is a broad survey of recent literature relevant to physiological interactions that have been demonstrated to occur or are likely to occur within the AP. Emphasis will be placed on studies in the past 7 yr, and the observations will be noted from two perspectives, in terms of the factor being studied and in terms of the cells involved. The aim is to produce a clear and worthwhile introduction to the subject and provide basic illustration of most of the best characterized interactions. Beyond that, this review is intended to provide a point of departure for further investigation of the literature about specific intrapituitary interactions. For important material published before 1992, the reader of the present review is often referred to an Endocrine Reviews article that appeared in that year (1). This has less to do with immodesty than a desire to keep the present review succinct. Since a number of topics relevant to intrapituitary interactions have also been reviewed recently, either as such or as part of a treatment of pituitary physiology from another perspective, reference to these has been cited in the present review. These include a number of other reviews on interactions in the AP, focused on the intrapituitary actions of peptides (2), components of the renin-angiotensin system (3), cytokines and growth factors (4), and activin and follistatin (5, 6, 7, 8, 9), and the use of reaggregate cultures to study intrapituitary interactions (10).
In this review there are two basic units. In the first unit the sections are delineated according to intrapituitary factor, and the discussion of each factor generally includes (in the following order): evidence of synthesis or secretion for the factor or its receptors within the AP; reports of how the genetic expression/biosynthesis/secretion of the factor or its receptors may be subject to physiological regulation; and description of the actions of the factor within the AP.
For many factors this circumstantial evidence provides a basis on which intercellular interactions may be presumed to occur; at least it demonstrates the potential for certain interactions. It does not prove or provide direct evidence that an interaction does occur or furnish support for any physiological role of the interaction.
In other cases the weight of currently available results provides more
substantial evidence, justifying the presumption of an intrapituitary
interaction. One example of such evidence is a change in the secretion
rate for a hormone caused by specific immunoneutralization of an
endogenous factor in a closed in vitro system. Addition of
an antiserum with high affinity for galanin decreases secretion of PRL
in a closed culture of dissociated AP cells, directly suggesting that
galanin of AP origin normally acts to maintain secretion of PRL
thorough an autocrine-paracrine mechanism (11). Other examples of such
evidence include direct demonstration that such factors are secreted
(as opposed to simply found or synthesized) by AP cells or altered
behavior in vitro by AP cells of transgenic animals that
over- or underexpress a putative paracrine factor. In cases of factors
where such evidence exists, particularly coming from multiple
approaches or multiple groups of investigators, a separate subsection
is included to emphasize the high likelihood, even at this point, that
the compound acts as a physiological intrapituitary factor. Figures 1
, 2, 3, 4, and 5 illustrate a number of interactions for
which substantial information exists that the locally produced factors
are acting physiologically within the AP.
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A note on the concentration dependence of some effects: The concentration-response relationships of a number of factors covered in this review reveal effects on AP cells under varying conditions (as, for example, in Section I). These include 1) only at very high (e.g., micromolar) concentrations; 2) with a biphasic response curve; and 3) with opposite effects, depending on concentration. Such observations are noteworthy in the context of local intercellular interactions. The concentrations of putative intercellular factors in the vicinity of the cells in which they are synthesized are likely to vary over an extremely wide range. This is particularly true of the systemic hormones, some of whose concentrations must be high enough within the AP to result in concentrations in the low nanomolar range in the peripheral circulation even after dilution in the blood, whereas at other times secretion by individual cells must be markedly suppressed. In all cases, concentrations within the AP will vary exponentially over time and as a function of distance from the source cell.
Because the pattern in which AP cells are exposed to paracrine factors is different to endocrine type exposure, a number of realizations should be noted in interpreting observations reported in this paper.
1. Effects observed to occur only at high concentrations may be physiologically relevant because of the levels encountered by target cells located adjacent to the source cells for a given factor.
2. AP cells may be chronically exposed to a factor secreted by an adjoining cell, and the normal response to that factor is thereby down- (or up-) regulated.
3. The "cocktail" of AP intercellular factors to which AP cells are normally exposed is likely quite different to that of peripheral cells. Thus, the media used for in vitro experiments may include or omit compounds, other than the factor(s) under study, that would normally modulate the activity of the cells in vivo. For this reason, observations, such as those differences observed in the behavior of cells in serum-free vs. serum-supplemented media, are quite interesting.
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II. Factors That Are Potential Paracrine Messengers in the Anterior Pituitary (AP) |
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TopAbstractI. IntroductionII. Factors That Are...III. Intrapituitary Interactions...IV. ConclusionReferences |
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. Table 2 contains
citations of recent observations that have localized the sites of
origin and activity within the AP of these factors.
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A. -MSH
-MSH is most commonly characterized as a cleaved product
of POMC, secreted by melanocytes of the intermediate lobe of the
pituitary and acting systemically in certain species to increase skin
coloring. The potential for AP cells to synthesize and secrete MSHs has
been studied (reviewed in Refs. 1, 2, 12), and -MSH is known to
stimulate PRL secretion.
A number of recent developments have been reported on lactotroph
function and -MSH. In addition to acting on its own, -MSH has
been found to increase the PRL-secretory responses to TRH or ATP (13).
Two other reports have noted that -MSH may act only on subsets of
lactotrophs. In one, -MSH was shown to increase calcium entry into a
subset of lactotrophs; in the other, using immunocytochemistry and
autoradiography, it was found that binding of -MSH is also limited
to a subset of PRL-positive cells (13, 14). In pituitaries of rats and
sheep the effect of -MSH is probably mediated by MC5 receptors; in
mice it is likely MC3 (15).
A related peptide, 
3-MSH, has also been found
to influence lactotroph function. 3-MSH, whose
amino acid sequence constitutes a segment of
POMC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74), was found to have the same mitogenic
effects as the larger peptide (see Section II.X, below),
albeit with lower potency (16).
B. -Subunit
The glycoproteins LH, FSH, and TSH are each composed of a common
-subunit and a specific ß-subunit. Although the -subunit is
acknowledged to have no systemic endocrine role by itself, it has been
observed to stimulate the differentiation of lactotrophs (17, 18). In bullfrog pituitary cells there is direct evidence for secretion
of -subunit, and -subunit stimulates secretion of PRL (19).
Further evidence for an action of gonadotrophs or products of
gonadotrophs on lactotrophs comes from recent studies with
gonadotroph-deficient transgenic mice. In the absence of gonadotrophs,
engineered by the expression of diphtheria toxin in cells with active
-subunit promoters, there is also a decrease in the number of
lactotrophs (20). Although the lactotroph-deficient phenotype in the
transgenic mice may be the result of diminished -subunit, it may
also involve other change associated with the presence of fewer
gonadotrophs.
C. Activin
The actions on pituitary cells of activin and the control of
activin biosynthesis and secretion within the AP are well described and
have been reviewed recently (including Refs. 5, 6, 7, 8, 9). A few recent
observations on activin are noteworthy in terms of the physiology of
activin. Pituitary levels of activin B mRNA expression correlate with
the plasma FSH levels characteristic of various breeds of swine (21).
In in vitro studies of female rat AP cells, treatment with
activin has been shown to increase both the numbers of cells secreting
FSH as well as the amount of FSH secreted per cell, and to inhibit both
the amount of PRL and numbers of cells secreting PRL (22). Biochemical
interactions between follistatin and activin molecules have long been
documented, forming the basis for the theoretical modulation of activin
activity by follistatin. In a study of extracts of pituitary tissue,
follistatin has been found bound to activin in the in situ
condition (23). Local activin may play a key physiological role in the
pituitaries of a wide range of vertebrates in addition to the more
commonly studied species, as an immunoreactive activin/inhibin
ßB chain has been detected in the gonadotrophs,
thyrotrophs, and somatotrophs of Xenopus (24).
D. Adenosine, ATP
Adenosine and ATP are produced by virtually all cells, so the
likelihood that either might act on neighboring cells is very high.
Measurable quantities of ATP are secreted by AP cells (25). In
gonadotrophs, ATP has been shown to stimulate flux of calcium and
increase LH secretion (26). Similarly, ATP and UTP were reported to
increase secretion of LH by rat pituitary cells (27). Other studies
have demonstrated an effect of ATP on calcium flux in all types of
pituitary cells (28), and evidence for the presence of specific ATP
receptors has been demonstrated in the rat pituitary by RT-PCR (29).
One mechanism of action of ATP in the pituitary involves specific, ATP-sensitive potassium channels, where ATP stimulates the closure of such channels (30). In contrast, in the absence of ATP, potassium efflux increases and the cells are thereby hyperpolarized (30). An extensive review of the literature on the molecular biology of these channels has been published recently (31). Whether this mechanism functions in the action of ATP on neighboring pituitary cells, or only within cells, remains to be elucidated.
In addition to the secretion of LH, ATP stimulates PRL secretion. Studies involving the reverse hemolytic plaque assay provide a potential physiological role in the pituitary for extracellular ATP (25). Secretory patterns for ATP parallel those of PRL in response to at least two factors: TRH increases, and bromocriptine decreases the secretion of both ATP and PRL. Although the parallel secretory responses could be the result of cosecretion from secretory vesicles, the observation that exogenous ATP stimulates PRL secretion would be consistent with the possibility of ATP action playing an intercellular role in the responses to TRH or dopamine.
Physiological activity of endogenous ATP. Evidence that endogenously produced ATP reaches neighboring cells at sufficient concentration to act physiologically comes from a number of different approaches. As noted above, ATP is secreted in measurable amounts by AP cells in vitro (25). In addition, blockade of ATP receptors or accelerated enzymatic metabolism of endogenous extracellular ATP decreases PRL secretion by AP cells in vitro (25).
Adenosine also has been reported to stimulate secretion of PRL in an action mediated by A1 type receptors (32). It also inhibits secretion of FSH (32). In another study, adenosine was reported to inhibit both LH and FSH secretion, under basal and GnRH-stimulated conditions (33).
E. Bombesin and gastrin-releasing peptide (GRP)
Bombesin and GRP are two structurally related peptides, known to
be synthesized in the AP. In the rat AP, GRP mRNA has been detected by
RT-PCR and Northern analysis (34). Bombesin and GRP protein have also
been found in goldfish pituitaries, where bombesin increases the
secretion of GH and the gonadotropin GtH-II (35). In rat APs GRP has
also been localized by immunocytochemistry to the corticotrophs and
lactotrophs (36). Binding sites for bombesin are present in rat AP,
primarily on somatotrophs and lactotrophs (37).
Physiological activity of endogenous GRP. A number of recent observations are helping to delineate the physiology of this peptide. GRP is reported to inhibit basal and TRH-stimulated secretion of TSH in rat hemipituitaries; perhaps more significantly, treatment of the same tissue with GRP antagonists increases secretion of TSH, consistent with a role for endogenous local GRP (38). The related peptide neuromedin B appears to play a similar role (Section II.T, below).
F. Brain-derived neurotrophic factor (BDNF)
mRNA for BDNF and for trkB, a protein associated with its
receptor, have been detected in rat AP by Northern analysis and
in situ hybridization (39). Further studies have noted
decreases in expression levels of trkB mRNA with aging (40) and
increases in levels of BDNF mRNA in AP cells after stress of the
animals (41). Immunocytochemical methods have been used to identify
BDNF protein in pituitary cells and colocalize it with TSH (42, 43).
The biological role of intrapituitary BDNF remains undelineated,
although, given the role played by BDNF in development, it may be quite
important.
G. Calcitonin gene-related peptide (CGRP)
CGRP immunoreactivity is present in AP cells (44, 45). More
recently, attention has shifted to the actions of CGRP on pituitary
cells. Some significant observations are those of stimulatory activity
on ACTH (46) and interleukin-6 (IL-6) (47). Given the action of IL-6
itself on ACTH secretion (reviewed in Refs. 1, 48), these
observations may indicate the existence of a potentially very complex
system, involving CGRP and interleukins, that influences ACTH
secretion.
H. Eicosanoids
Defining the potential role of metabolites of arachidonic acid
(eicosanoids) as intercellular signals is somewhat problematic. These
molecules clearly act as intracellular signals and it is
difficult to distinguish inter- vs.
intracellular actions of the eicosanoids in AP cells.
Indirect evidence for intercellular interactions of eicosanoids
generally takes the form of an effect by a particular eicosanoid,
exogenously added, at a concentration at which the compound has been
observed to be present among AP cells in the same or similar in
vitro conditions. One relevant question in such cases is whether
the observed concentration is physiological or an artifact of
the experimental system. Another problem in ascribing
intercellular actions to eicosanoids is the difficulty of
studying the effect of blockade of the actions of extracellular
eicosanoids. Experiments in which the local biosynthesis of various
metabolites of arachidonic acid is blocked have proven useful in
studying the AP actions of eicosanoids. However, the most parsimonious
interpretation of such data must be to ascribe the action of the
inhibited eicosanoid to an intracellular role. With this as
a guideline, a number of observations on the activity of eicosanoids on
AP cells will be described, as they may suggest involvement in
intercellular actions.
A number of unidentified intercellular factors influence corticotrophs (1). Given the range of actions of metabolites of arachidonic acid in the AP, eicosanoids may play an intercellular role. Early studies with inhibitors of the various metabolic pathways suggested that lipoxygenase-generated metabolites stimulate, and cyclooxygenase products inhibit, ACTH secretion (49, 50). More recent studies suggest that metabolites of C450 enzymes also stimulate ACTH secretion (51).
Eicosanoids also alter the function of gonadotrophs. In the gonadotroph
cell line T3–1, treatment with arachidonic acid, 5-HETE, or
leukotriene C4 increases the levels of LH
-subunit mRNA, suggesting a stimulatory action (52).
I. Endothelins (ETs)
The ET family of peptides, including ET-1, ET-2, and ET-3, has
been found to be produced and likely to act within the AP, primarily as
an inhibitor of lactotrophs. Studies with reverse hemolytic plaque
assays have demonstrated that lactotrophs also secrete ETs (53). A
study that has updated these observations has provided further
intriguing results, suggestive of multiple molecular interactions (54).
ET-1 and ET-3 were observed to decrease PRL secretion by rat AP cells
cultured in serum-supplemented medium. Similarly, at relatively low
concentrations, the ETs decreased PRL secretion in cells cultured in
serum-free medium. However, in cells cultured in serum-free conditions
ET-1 and ET-3 stimulated PRL secretion, when present at
relatively high concentrations. As noted in the
Introduction, the changes in response of AP cells as a
function of the concentration of ETs and the presence of serum factors
may be highly relevant in terms of how the AP responds in
vivo. Further elucidation of the interactions of the various
factors involved in the responses to ETs will define their role in
secretion of PRL.
Physiological activity of endogenous ET. One of the most elegant demonstrations of a likely physiological action of ETs within the AP is described in a recent study (53). As previously noted, the investigators were able to demonstrate secretion of immunoreactive ET-1 by AP with a plaque assay. An inhibitory effect of endogenous ET on PRL secretion was also demonstrated by increases in PRL in response to pharmacological blockade of ETA, but not ETB, receptors and by inhibition of local ET-convertase enzyme.
J. Epidermal growth factor (EGF)
As with many of the peptides termed growth factors, EGF was
characterized chemically, and the actions of the peptide were first
described several years ago. Since the discovery of evidence of its
biosynthesis in pituitary cells, a measure of attention has been paid
to potential activity of EGF within the pituitary. There is now
abundant evidence of regulated production of EGF and its receptors in
AP cells. The demonstrated actions of EGF on AP cells are consistent
with the presence of both a direct role of EGF on secretory cells and
an indirect role in which EGF influences the response of secretory
cells to other factors. The demonstrated direct actions of EGF range
from altering secretion rates of hormones to stimulation of mitosis and
differentiation of cells. This subsection will describe the latest
findings on the control of EGF in the AP and its role in the physiology
of the AP.
All the components necessary for a local EGF system, including expression of mRNA and protein for EGF and EGF receptors, have been detected in the AP. EGF has been shown to be secreted by about 20% of AP cells (55, 56, 57). In lactating rats, a distribution has been described, wherein a substantial fraction of all secretory cells also secrete EGF (PRL, 27%; GH, 20%; LH, 18%; FSH, 14%; TSH, 14%; ACTH, 5%) (56). In contrast, in immature rats, the majority of EGF-secreting cells are LH-positive (57). Other groups have reported EGF mRNA in adult male rat AP in GH- and gonadotropin-positive cells (58), and EGF protein in all cell types in human pituitaries (59).
Receptors for EGF are also present on many AP cells. EGF receptors have been reported to be present on 48% of AP cells (55). In male rat AP, the distribution of cells with receptors for EGF apparently extends to subsets of all the secretory cells (58) and varies in female rats as a function of the estrous cycle (60). High and low affinity binding of radiolabeled EGF can be demonstrated in AP cells (61).
The synthesis and secretion of EGF and the functional expression of its receptors are subject to dynamic regulation. As noted above, EGF receptor populations vary with the estrous cycle (60). Other physiological changes also alter the pituitary EGF system. Exposure of adult male rats to cold stress or restraint stress, but not ether stress, increases levels of EGF mRNA in the pituitary (58, 62). In immature female rat AP cells, GnRH is reported to increase the amount of EGF secreted per cell (57). In sheep pituitary cells, exposure to any of the following: estrogen, T3, cortisol, EGF itself, basic fibroblast growth factor (bFGF), transforming growth factor (TGF)-ß, or phorbol ester, increases the affinity and decreases both the binding capacity for EGF and mRNA of the high-affinity EGF receptor (61). Estradiol can decrease the fraction of gonadotrophs with EGF receptors (63). Further evidence that EGF itself plays a role in regulating EGF receptors in FSH-expressing cells comes from studies with serum-supplemented incubation medium. While serum supplementation is associated with increases in the numbers of LH- and FSH-positive cells with EGF receptors, removal of serum or immunoneutralization of EGF in the serum will prevent the increase in FSH-positive cells with EGF receptors (63).
A number of actions of EGF on pituitary cells have been characterized. In rat AP cells, EGF increases the presence of receptors for GnRH and the LH-secretory response (64). Evidence that local EGF is responsible comes from the observation that the same effect can be caused by adding AP cell-conditioned medium to a second population of AP cells, and that this effect is eliminated by specific immunoprecipitation of EGF from the conditioned medium. EGF stimulates TSH secretion by fragments of rat pituitary (65). In the cell line GH4, which secretes PRL and very much less GH, EGF increases synthesis and secretion of PRL (66). Interestingly, in the same cell line EGF also induces the functional expression of dopamine D2 receptors, which they normally lack, and these receptors are active in terms of coupling to potassium channels (67). In other experiments with GH4 cells, EGF increases adenosine A1 receptors and mRNA for TRH receptors (68, 69).
Other reported actions of EGF in the pituitary are related to growth and differentiation. In an enriched population of corticotrophs from male rats, EGF increases uptake of bromodeoxyuridine (BrDU) (70). After a 1-h exposure to CRH and EGF, 47% of corticotrophs are BrDU positive. In sheep pituitary cells, treatment with EGF increases the uptake of radiolabeled thymidine, with the majority of labeled cells being gonadotrophs or cells that did not stain for any of the pituitary hormones (71). Exposure of GH3 cells, which secrete both PRL and GH, to EGF for 6 days in culture increases the fraction of the cells that exclusively secrete PRL from 0.5 to 8.0% (72). Similar changes occur when normal rat AP cells are cultured 2 days with EGF; in addition, PRL secretion is increased in these cells (72).
Physiological activity of endogenous EGF. As noted above, at least one of the recently described actions of EGF can be associated with endogenous local peptide. The action of EGF on the response of AP cells to GnRH can be eliminated by immunoprecipitating EGF from the AP cell-conditioned medium (64).
K. Follistatin
As with activin, the reader is directed to specialized reviews for
broad discussions in this area (including Refs. 6, 7, 8, 9). The present
review will be limited to recent developments that add physiological
perspective to the actions of follistatin in the AP. In castrated male
monkeys in vivo, intravenous infusion of follistatin was
found to inhibit the FSH response to activin, but not to GnRH,
consistent with a modulatory role for follistatin acting only as an
activin-binding protein (73). Along the same lines, the reduction of
FSH ß mRNA associated with exposure to another factor, pituitary
adenylyl cyclase-activating peptide (PACAP), is also associated
with increased follistatin gene expression (74). Interleukin-(IL)-1ß,
which was shown to stimulate follistatin secretion, was also observed
to attenuate the FSH response to activin A (75). The stimulatory effect
of GnRH on FSH ß mRNA was studied in perifused male rat AP cells,
using various pulse patterns of GnRH (76). Treatment of the cells with
GnRH at a frequency of one pulse per hour stimulated FSH ß mRNA and
not follistatin mRNA. In contrast, when the frequency of the GnRH
pulses was increased, so were the levels of follistatin mRNA, and the
increase in levels of FSH ß mRNA was attenuated. When treatment with
follistatin was included during hourly pulse treatments with GnRH, the
increase in FSH ß mRNA observed earlier was blocked. Taken together,
these data are consistent with activin playing a mediating role in the
response to GnRH, and with endogenous follistatin being an increasingly
important intrapituitary modulator of the action of GnRH on expression
levels of FSH ß mRNA as pulse frequency increases.
L. Galanin
In terms of its potential physiological activity, galanin is one
of the better characterized paracrine factors in the pituitary. Much
recent work has focused on galanin actions relative to the activity of
corticotrophs and lactotrophs.
Because of the known physiological relevance of galanin, it is important to determine the pituitary cells that produce it (12). As yet, there is no clear picture of the localization of galanin in the pituitary. A number of studies have colocalized galanin with PRL in, at least, a fraction of the lactotrophs (11, 77, 78). These and other studies have reported colocalization in other cells in addition to or instead of lactotrophs. One study, employing cellular immunoblotting technology with rat AP cells, localized galanin with PRL or ACTH (77). In the normal and transgenic (human GHRF-expressing) mouse AP, immunocytochemical techniques were used to demonstrate the colocalization of galanin with GH, PRL, or TSH (78, 79). In humans galanin secretion has been measured in cultures of ACTH-secreting tumors (80). Recently, using immunocytochemical techniques, galanin also has been reported to be present in nerve fibers in monkey and canine pituitaries in close proximity to all types of secretory cells (81).
The regulation of galanin synthesis and secretion in AP cells is also an area of ongoing investigation. In vivo administration of the synthetic glucocorticoid dexamethasone increases galanin mRNA in rat AP (82). Pituitary cells obtained from transgenic mice that overexpress human GHRH secrete more galanin than those obtained from control mice, as demonstrated by cellular immunoblotting (79). A number of studies have also established a role for the thyroid in maintaining pituitary galanin content (83, 84). Vasoactive intestinal peptide (VIP) increases galanin secretion by pituitary cells (85). PRL has been reported to decrease levels of galanin and VIP mRNAs (86). Arguably, estrogens exert the most important influence on galanin activity in the pituitary, where estradiol positively regulates galanin-expressing cells in a number of ways, including the amount of galanin protein and mRNA in pituitaries and the number of galanin-secreting cells (85, 86).
The local pituitary action of galanin is most closely associated with the secretion of PRL. Transgenic mice that overexpress galanin have larger pituitaries (females) with a higher fraction of lactotrophs and greater expression levels of PRL mRNA per lactotroph (87). Taken one physiological step further, pituitaries of transgenic mice that do not express galanin have decreased PRL protein and mRNA, and the females do not lactate (88). In normal rat AP cells and the rat lactotroph cell line 235–1, inhibition of endogenous galanin by immunoneutralization decreases PRL secretion and the mitogenic effects of estradiol (11, 85). In the interaction between VIP and galanin, it was found that VIP increases secretion of galanin; and the attenuation of PRL secretion by immunoneutralization of VIP does not occur in populations of separated lactotrophs [indicating that VIP comes from other cells (85)].
Galanin has also been associated with secretion of GH (1). An interesting finding is that immunoneutralization of endogenous galanin decreases GH secretion from pituitary cells obtained from mice genetically engineered to express human GHRH (79).
In a study addressing the role of galanin in ACTH secretion, it was reported that treatment in vitro with either galanin or estradiol inhibits ACTH secretion by rat AP cells (77). In addition, immunoneutralization of galanin reverses the inhibitory action of estradiol, suggesting that endogenous galanin plays a role in mediating the effects of estrogens on ACTH secretion (77).
Locally produced galanin appears to inhibit GnRH-stimulated gonadotropin secretion in rat pituitary cells, as immunoprecipitation of endogenous galanin potentiates GnRH-stimulated LH secretion (89).
Physiological activity of endogenous galanin. The extensive studies of the actions of galanin in the AP provide strong evidence that galanin operates as an intrapituitary intercellular factor. As described above, a preponderance of evidence, including measurements of galanin protein and mRNA within AP cells and cellular immunoblotting of galanin secretion by AP cells (77), indicates that galanin is synthesized and secreted by AP cells, and the activity of galanin in the AP is tightly regulated. The potential physiological role of galanin is emphasized by the studies in which endogenous galanin was physically or functionally removed: the APs of galanin-deficient transgenic mice contain less PRL protein and mRNA, and females do not lactate (88); and in wild-type AP cells, immunoneutralization of endogenous galanin decreases PRL and GH secretion, increases GnRH-stimulated LH secretion, and reverses the action of estrogens on ACTH (11, 77, 79, 89).
M. GnRH
Several of the hypophysiotropic releasing and inhibitory factors
and hormones, originally thought to be synthesized only in the
hypothalamus, have been reported to be synthesized and secreted by
pituitary cells (12, 90). GnRH has been reported to be produced by AP
cells, and recently GnRH mRNA was found in human pituitary tumors (91, 92).
Studies of the action of GnRH on gonadotrophs have been reviewed in depth (93). The implications of local production of these potent factors are self-evident. Among the most recent developments in the area of pituitary production of GnRH is the observation that GnRH induces differentiation of gonadotrophs and thyrotrophs among fetal rat AP cells (18). Although the effect in vivo may be due to hypothalamic GnRH, the uneven distribution of the cells suggests involvement of some local factors.
Physiological activity of endogenous GnRH. As evidence that local GnRH mediates actions within the AP and further to the role of GnRH in development, it is noteworthy that GnRH mRNA has been detected in extracts of Rathke’s pouch of rat fetuses at 12 days of gestation by RT-PCR (94). In explants of Rathke’s pouch, pharmacological blockade of GnRH receptors during culture decreases the area of PRL staining (94).
N. GH
If there is any class of compounds about which there is no doubt
as to the synthesis and secretion in pituitary cells, it is the
pituitary hormones. Aside from their systemic actions, recent work has
been directed at delineating activity of the pituitary hormones within
the pituitary. An inhibitory action of GH on somatotrophs has been
known for some time. Recently, receptors for GH have been localized
within the pituitary by immunocytochemistry and in situ
hybridization to somatotrophs, lactotrophs, and gonadotrophs (95).
Radiolabeled GH is taken up by somatotrophs and gonadotrophs (96).
Transgenic mice, engineered to overexpress GH, have altered pituitary function. The excess GH in these animal models is not necessarily produced in the pituitary and thus may be acting indirectly; nevertheless, the effects of elevated GH, regardless of its origin, are worth noting as they may mimic concentrations normally encountered only by AP cells adjacent to GH-secreting cells. Compared with controls, transgenic mice, expressing the bovine GH gene, produce pituitaries with less FSHß and LHß mRNAs, less FSH protein, higher unstimulated LH and FSH secretion in perifusion in vitro, and a decreased gonadotropin response to GnRH (97). Interestingly, mice expressing the human GH-variant B produce pituitaries that have a decreased rate of unstimulated PRL secretion and an increased LH-secretory response to GnRH in vitro (98).
O. Insulin-like growth factor-I (IGF-I)
The discovery within the AP of the biosynthesis and activity of
IGFs has led to further research aimed at defining the potential role
of an intrapituitary IGF system. An expanding number of observations
provide evidence for multiple actions of IGFs in the APs of a variety
of species. These include direct effects of IGFs on the proliferation
of secretory cells and the synthesis and secretion of pituitary
hormones. There are also reports of a stimulatory effect of IGF-I on
VIP, which may mediate further intercellular interactions. As more
becomes understood about the actions of IGFs and the control of
secretion of IGF in the AP, the potential physiological roles of
intrapituitary IGFs is becoming clearer. The purpose of this section is
to describe recent findings on the expression and actions of IGF-I in
the AP.
IGF-I is synthesized in AP cells. In mice, IGF-I protein and mRNA have been localized to somatotrophs, and IGF-I receptor mRNA has been localized to corticotrophs and somatotrophs by in situ hybridization (99). In rat pituitaries, IGF-I mRNA was found by in situ hybridization to be distributed throughout the pituitary, primarily in cells thought to be typical of folliculostellate cells (100). Interestingly, the authors of the latter study interpret the sum of the data to suggest that although some cells produce both GH and IGF-I, there is no particular correlation of IGF synthesis with somatotrophs. In the fish species tilapia in further contrast, IGF-I has been colocalized in cells with gonadotropin GtH-II (101).
Evidence for the synthesis of IGFs has also been found in fetal APs. In the pituitaries of fetal rats of 14–15 days gestation, IGF-II mRNA, but not IGF-I mRNA, was detected by in situ hybridization (102). In the fetal sheep pituitary, mRNA for IGF-II is also detectable by Northern blot analysis, and IGF-I and IGF-II protein have been detected by immunocytochemistry (103).
In terms of the regulation of expression of mRNA for IGF-I and IGF receptors, and the synthesis of the factor in the AP, several interesting findings have been reported. In rats, streptozotocin-induced diabetes increases levels of IGF-I protein and mRNA in the pituitary (104). Binding of labeled IGF-I in rat AP slices varies as a function of exposure to estrogens and or the phase of the estrous cycle although, as the authors note, this may reflect changes in IGF-binding proteins as well as receptors (105). Also, in rats in vivo administration of IL-1 is associated with a decrease in pituitary IGF-I content (106). Along these lines it may be noteworthy that IGF-I is also reported to decrease GH secretion (see below), and IL-I has been reported to increase GH secretion (107, 108), all of which fits a scenario in which IGF-I mediates the action of IL-1 on GH secretion.
The actions of IGFs in the pituitary are varied. IGF-I has been reported to increase the proliferation rate for corticotrophs and lactotrophs (99, 109). On the other hand, IGFs were known to inhibit GH secretion even before they were called IGFs. In this regard, the inhibitory effect of IGF-I has been shown recently to increase in terms of sensitivity between the fetal and neonatal periods in swine pituitary (110). Another study has demonstrated in vivo that the GH-inhibitory action of IGF-I is direct on the pituitary (111).
A recent study in rat AP cells further elucidates IGF-I actions in the pituitary (112). Three-hour incubations with IGF-I result in increases in VIP content and secretion of PRL; after 48 h, mRNA for VIP is also elevated as is PRL secretion and content, but not PRL mRNA. In the same studies, concomitant immunoneutralization of VIP blocked the action of IGF-I on PRL, but not (inhibition of) GH, suggesting that IGF-I stimulates lactotrophs indirectly via an increase in VIP. Another illustration of potential multifactorial intrapituitary influences is in the observation that in the PRL-secreting cell line GH4 estradiol stimulates IGF-I production, when the cells are plated at low density (10,500 cells/cm2) but not at high density (42,000 cells/cm2) (113).
In other species local IGF-I may play different roles. In tilapia pituitary cell cultures enriched in somatotrophs, local IGF-I is reported to inhibit apoptosis that would otherwise occur (101). In the AP of juvenile female eels, IGF-I stimulates the production and secretion of gonadotropin GtH-II (114).
P. Interleukin-6 (IL-6)
Intrapituitary generation and action of cytokines has been the
subject of investigation for several years, and a number of cytokines
have been identified as potential intercellular mediators. The actions
of cytokines in the AP are also described in a number of recent
reviews. Two are particularly relevant to paracrine interactions (4, 48).
This review will focus on developments concerning three cytokines, IL-6, IL-11, and leukemia inhibitory factor (LIF). Since the three cytokines have been implicated in the secretion of ACTH, thereby activating adrenal steroidogenesis, intrapituitary actions of cytokines may represent one aspect of the endocrine-immune interactions that are believed to be a key physiological regulatory mechanism (115).
IL-6 now has been detected in the APs of a number of species, including swine (116). Immunocytochemical studies in murine AP have produced evidence of IL-6 localization in folliculostellate cells (117). IL-6 mRNA has now been detected by RT-PCR, and exposure of pituitary cells to endotoxin increases both IL-6 mRNA and IL-6 secretion. IL-6 has also been found to be secreted by cells of the rat intermediate lobe, which may also contribute to local control of ACTH, if transported via the short portal vessels (118).
Regulation of IL-6 secretion by AP cells has been investigated. Exposure of AP cells to IL-1 stimulates secretion of IL-6 by pituitary cells (1), an interaction that may be important in regulating ACTH responses. Lysophosphatidylcholine, a second messenger involved in responses to IL-1, also stimulates secretion of IL-6 by rat AP cells directly (119). Other factors that might interact with cytokines involved in the secretion of ACTH include PACAP and CGRP, which stimulate IL-6 production in rat AP cells (47). CGRP also increases ACTH secretion, which raises the possibility that IL-6 mediates the action of CGRP on corticotrophs (46).
Q. Interleukin-11 (IL-11)
IL-11 has also been found to be part of an intrapituitary
regulatory system (120). IL-11 mRNA has been detected in AP tissue by
RT-PCR. IL-11 receptor mRNA has been found by Northern analysis in the
corticotrophic cell line AtT20 cells as well as
in normal human and murine pituitary tissue. Exogenous IL-11 increases
ACTH secretion and levels of POMC mRNA in AtT20
cells.
R. Leukemia inhibitory factor (LIF)
Since evidence of production of LIF by pituitary cells was found
several years ago (121), the potential for LIF to act locally in the
pituitary has been investigated by a number of groups. In rat AP,
dexamethasone down-regulates LIF mRNA (122). Subsequently, LIF and LIF
receptor mRNA were found to be up-regulated by exposure of animals to
endotoxin (123). Originally localized to folliculostellate cells in
bovine AP (121), LIF has been localized in later studies to subsets of
all secretory cells in human fetal AP (124) or to gonadotrophs and
thyrotrophs in ovine AP (125).
Physiological activity of endogenous LIF. LIF stimulates ACTH secretion by AtT20 and normal ovine pituitary cells (124, 125), and ACTH secretion in vitro is decreased under certain conditions by immunoneutralization of endogenous LIF (124, 125). Physiological relevance has been added to the actions of LIF by experiments in which an attenuated hormonal response to stress or IL-1 has been observed in genetically LIF-deficient mice (126, 127, 128). In contrast, transgenic mice that overexpress LIF in the AP have retarded development of the AP and increased numbers of corticotrophs (129).
S. Nerve growth factor (NGF)
The study of the physiology of NGF has been expanded by assessing
its biosynthesis and actions within the AP. There is an accumulating
body of literature describing the localization and regulation of NGF
expression within the pituitary as well as its actions and potential
roles.
NGF is produced in and secreted by cells of the AP. Immunoreactive and bioactive NGF has been measured in medium exposed to pituitary cells (130), and NGF mRNA has been detected in pituitary cells (42). Some investigators have reported colocalization of NGF with PRL (131). Others have reported colocalization with TSH (132), an association that persists in pituitary cells in culture (133). Another group (134) has found a broader distribution of NGF immunoreactivity (10% of corticotrophs, 64% of thyrotrophs, 75% of LH gonadotrophs, 51% of somatotrophs, and 42% of lactotrophs), while a fourth group (135) using adult male macaque pituitaries and acknowledging the presence of NGF in the pars distalis, reported colocalization in cells that stain negatively for the six pituitary hormones.
Secretion of NGF appears to be influenced by numerous factors. In rat
AP cells in culture, IL-1ß was reported to stimulate, and GHRF, tumor
necrosis factor-, and bFGF to inhibit, NGF secretion (130).
Pituitaries from hyperthyroid rats have been observed to contain more
NGF than those of control rats (136).
It is very likely that NGF acts physiologically on pituitary cells also. Receptors for NGF and NGF receptor mRNA have been found in pituitary cells. In situ hybridization studies have shown the low-affinity neutrophin receptor p75 mRNA in the developing rat AP, with a positive signal in all cells of Rathke’s pouch at day 13 of gestation and in declining numbers thereafter (137). Similarly, in the monkey, pituitary cells with NGF and NGF receptor (p75) are more numerous in fetal than postnatal life (135).
NGF receptor immunoreactivity was found in postnatal rat pituitaries (134). Consistent with the studies cited above, these investigators observed no p75 NGF receptor, but, significantly, did detect the high-affinity, physiological NGF receptor gp140trkA, localized to corticotrophs (33%), thyrotrophs (45%), gonadotrophs (44%), somatotrophs (23%), and lactotrophs (41%).
Studies have provided evidence that NGF plays a key role in mitosis and differentiation of AP cells, which is relevant to the appearance of NGF and its receptor in fetal life. One series of studies has provided evidence that NGF is involved in the differentiation of cells into lactotrophs. NGF increases, and immunoneutralization of endogenous NGF decreases, the proportion of lactotrophs in cultured neonatal rat pituitary cells (138). NGF also inhibits proliferation of GH3 cells, while increasing PRL secretion, decreasing GH secretion, and causing the lactotroph-specific D2 dopamine receptor to be expressed (139). Another study has demonstrated an increase in mitotic activity in neonatal rat pituitary reaggregates in vitro by lactotrophs and other cells in response to NGF (140).
T. Neuromedin B
This peptide belongs to the bombesin/GRP family. It is synthesized
in AP cells (34). Neuromedin B inhibits secretion of TSH, when added
exogenously in vitro, whereas immunoneutralization of
locally produced neuromedin B increases TSH secretion (141). Similar
experiments and results have been described for GRP (see Section
II.E). As a part of studies to establish the local role of
neuromedin B, recent experiments have demonstrated in rats that fasting
is associated with decreased, and diabetes associated with increased,
levels of neuromedin B in the pituitary (142).
U. Nitric oxide (NO)
Since the discovery of NO as a signal molecule, efforts have been
directed at assessing its potential as a local mediator in the
pituitary. Because of the short half-life of NO, the presence of the
enzyme nitric oxide synthase (NOS) has been used to localize the site
of synthesis of NO. Numerous studies have provided evidence for the
presence of NOS in pituitary cells. Gonadotrophs and folliculostellate
cells have been reported to contain NOS (143). The neuronal isoform of
NOS and its mRNA were found in pituitary adenomas and in lower
quantities in normal human pituitaries, localized by
immunocytochemistry and in situ hybridization to secretory
as well as folliculostellate cells (144, 145). The endothelial isoform
of NOS was also detected in human pituitaries (144).
The presence and activity of NOS in the AP is also subject to
extrapituitary influence. In cultures of rat AP cells, interferon
(IFN)- increases the number of cells with identifiable quantities of
the inducible isoform of NOS (146). Morphological criteria and
experiments with separated populations of cells are consistent with the
NOS-containing cells being a subpopulation of folliculostellate cells
and some non-hormone-secreting cells (146). IFN also increases NO
production as measured by increases in the concentration of nitrates in
the incubation media (146).
Additional actions of NO in the pituitary have been studied by measuring changes associated with the addition of NO, NO donor molecules, or inhibitors of NOS (12). Among recent reports, blockade of NO synthesis was demonstrated to potentiate the LH-secretory response to GnRH (143). Interestingly, in these studies the NOS inhibitor N-methyl-l-arginine had no effect on LH in the absence of GnRH. This suggests that NO may play a role as a signal to terminate release of LH in response to GnRH, and that the NO involved in LH secretion either originates in gonadotrophs or requires the participation of gonadotrophs. NO may also influence secretion of PRL, although there are inconsistencies in some results. In two similar studies with rat hemipituitaries or dissociated AP cells, and treatments with NO donor molecules, NOS inhibitors, or the NO scavenger hemoglobin, the results were internally consistent for endogenous NO either to stimulate (147) or inhibit (148) secretion of PRL.
V. Neuropeptide Y (NPY)
NPY is another substance that is synthesized within the AP and has
been shown to alter the function of pituitary cells. NPY protein and
NPY mRNA are present in cells of the AP, and studies have extended the
identification to human pituitary cells (149). From studies in rats it
is known that the activity of NPY varies as a function of the estrous
cycle, and expression levels also change according to the steroid
environment (150). Compared with the pituitaries of immature female
rats receiving estradiol only for 2 days, those of female rats that
received an additional injection of progesterone on the third day have
elevated NPY protein and the same levels of NPY mRNA (150).
Thyroidectomy is also associated with increased NPY protein and mRNA
(151). Measurable quantities of binding sites for NPY are present in
human AP (152) as is NPY-Y1 receptor mRNA in sheep (153).
Other work in the past 7–8 yr has more fully defined the actions of NPY in the pituitary, although it is worth bearing in mind that these actions might not reflect the physiological actions of locally produced NPY, since NPY from the hypothalamus reaches the AP as well. Most studies on the effect of NPY on LH secretion are consistent with NPY having no effect by itself, but a potentiating action on the LH-secretory response to GnRH (154, 155, 156, 157). On the other hand, some studies have demonstrated stimulation of secretion of gonadotropin in response to NPY alone. In rat AP cells, LH secretion was reported to be stimulated by NPY at 10-6 M (158). Interestingly, effects in AP cells at high concentration are more likely to reflect actions of locally produced NPY on cells adjacent to the source cells, rather than NPY from the hypothalamus, which is subject to dilution in the blood. In goldfish pituitaries NPY (at nanomolar concentrations) stimulates gonadotropin II (GtH-II) secretion, an action that is potentiated in pituitaries from sexually immature fish by prior in vivo treatment with testosterone or estradiol (159, 160, 161). In terms of potentiation of the LH-secretory action of GnRH, the action of NPY was found to be prevented by inhibition of protein kinase C (154). In contrast, NPY was also found to attenuate the action of progesterone plus GnRH on LH secretion from rat pituitaries obtained at metestrus (155).
NPY also has a positive effect on FSH. In autotransplanted neonatal hamster pituitaries 7 days post surgery, the number of FSH-immunopositive cells is higher in glands from host animals that had been pulse-infused with NPY plus GnRH than from hosts that had been infused with either peptide alone or saline (162). NPY was also reported to potentiate the FSH-secretory action of GnRH in rat pituitary cell cultures (158). One potential mechanism by which NPY might potentiate the action of GnRH on gonadotrophs is by increasing the number of functional GnRH receptors (163).
NPY also stimulates GH secretion, as reported in studies with goldfish (159, 160, 161). PRL secretion is also influenced by NPY. The peptide inhibits PRL secretion and attenuates both the PRL-secretory and intracellular calcium flux responses to TRH in rat AP cells (164).
W. Oxytocin
More than a decade ago this peptide was discovered to be
synthesized in the pituitary; among its actions are stimulation of
secretion of PRL and LH. In recent years, oxytocin receptor mRNA has
been localized to lactotrophs (165). This reinforces the concept that
oxytocin of hypothalamic or local origin acts on the pituitary via
specific receptors; it also suggests that the action of oxytocin on LH
secretion (90) involves production of another local factor secreted by
lactotrophs.
X. POMC fragments
POMC, the biosynthetic precursor of ACTH, ß-endorphin, and a
number of other peptides, is synthesized in the AP. One fragment of
POMC, -MSH, was discussed above. A number of recent studies have
focused on the actions of other segments of the POMC molecule on
pituitary cells. POMC (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52), originally
isolated from hypothalamic extracts, was found recently to be a potent
inhibitor of PRL secretion (166).
The mitogenic activity of locally produced
POMC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76) on AP lactotrophs has been carefully
established in a series of studies with AP cells from 14-day-old female
rats, in which observations on the effects of the presence or absence
of other cell types on thymidine uptake in lactotrophs led to the
isolation of an active compound from medium conditioned by exposure to
AP cells. In an early study with reaggregates of dissociated AP cells,
enriched in gonadotrophs, it was found these latter cells secrete a
factor that increases thymidine uptake into DNA of lactotrophs and
corticotrophs and decreases uptake in somatotrophs (167). In the same
study, it was found that mixed cultures of all AP cells also produced
the factor in response to NPY or GnRH, whereas gonadotroph-deprived
cultures did not (167). Similarly, GnRH increased the total area of
cytoplasm and the number of cells containing PRL mRNA (168). In a
subsequent study, POMC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74) was found to be the
likely factor that stimulates the uptake of labeled thymidine into the
DNA of lactotrophs (169). Thus, in that study it was interesting that
the POMC fragment was initially isolated as an active fragment of
culture medium conditioned by exposure to reaggregates of enriched
gonadotrophs, rather than the cells that express POMC mRNA in
adulthood, the corticotrophs. In AP cells from 14-day-old rats
exogenous POMC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76) and 3-MSH were also found to stimulate the number
of lactotrophs incorporating labeled thymidine.
Physiological activity of endogenous POMC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76). In the above cited series of studies it was established that specific immunoneutralization of endogenous POMC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76) decreased thymidine uptake in lactotrophs of mixed cultures of AP cells (16).
Y. PRL
The full range of local actions of PRL within the AP are only
beginning to be understood. Receptors for PRL have been detected by
immunocytochemistry on all types of pituitary cells, with the highest
frequency of labeling being associated with somatotrophs (170).
GH3 cells are a cell line that secretes both PRL
and GH. Exogenous PRL increases the rate of proliferation, and
immunoneutralization of endogenous PRL decreases the rate of
proliferation of GH3 cells in culture, suggesting
a physiological role for endogenous PRL (171).
Physiological activity of endogenous PRL variant. A cleaved variant of PRL was reported to be mitogenic in rat AP cells (172). Immunoneutralization of the endogenous PRL variant decreases uptake of labeled thymidine into the DNA of gonadotrophs and thyrotrophs in reaggregates of pituitary cells of 14-day-old rats (172).
Z. Substance P (SP) and neurokinin A (NKA)
The synthesis by AP cells of SP, a tachykinin, has been known
since at least 1982 (173). Consideration of its role as a local factor
in the pituitary has been enhanced by studies that demonstrated its
secretion by pituitary cells (174). SP is a good molecule to use as a
model for local activity. It is secreted by a number of different
pituitary cells, it acts on a number of different cells, its secretion
is subject to regulation, and pharmacological blockade of endogenous SP
has a measurable effect—all of which suggest a role for locally
produced SP (174, 175, 176, 177, 178).
Immunocytochemical localization studies have placed SP in thyrotrophs [guinea pig (179)] or thyrotrophs and somatotrophs [rat (174)]. In rat pituitary cells, it is also thyrotrophs and somatotrophs that have been demonstrated to secrete SP (174). The association with thyrotrophs assumes further relevance in light of the observation that prior thyroidectomy increases the number of SP-secreting cells and the total amount of SP secreted but decreases the average amount of SP secreted per cell (178).
The Siberian hamster, a species noted for gonadal responses to changes in photoperiod, has more SP in the AP than the rat, and the abundance of SP varies inversely with the length of photoperiod (180). Changes in SP are mirrored in those of the related peptide NKA. The latter peptide is also involved in intrapituitary interactions, as blockade of NK2 receptors alters FSH and LH secretion, and immunoneutralization of endogenous NKA decreases secretion of gonadotropins by AP cells from Siberian hamsters (180).
SP has long been associated with secretion of GH and PRL (175). More recently, SP and VIP have been found to interact at the level of signal transduction mechanisms in enriched populations of lactotrophs (181, 182).
Physiological activity of endogenous SP. SP also influences LH secretion, both positively and negatively, as demonstrated in rat AP cells (177, 183). The results of the more recent study suggest that the estrogen/progesterone environment is a factor in determining the action of SP on LH secretion; and effects of blockade of the SP receptors (neurokinin NK1) by RP 67580 in the presence and absence of SP are consistent with SP acting via NK1 receptors and endogenous local SP playing a role in influencing LH secretion (177). In pituitaries of female Siberian hamsters, blockade of NK2 receptors, for which the presumed endogenous ligand is the related peptide NKA, results in increased secretion of FSH and an attenuated LH or FSH response to GnRH (177, 180). An intriguing consistency between the two studies with NK1 and NK2 receptor antagonists in rats and hamsters is the apparent dual nature of the endogenous tachykinin signal, being either stimulatory or inhibitory of gonadotropin secretion, dependent either upon the simultaneous presence of GnRH or SP. Taken together, the preponderance of evidence indicates that locally produced SP influences the secretion of gonadotropins and probably other hormones by neighboring cells.
AA. Transforming growth factors (TGFs)
These proteins were named initially for the ability to stimulate
phenotypic transformation and have since been found to act positively
and negatively on cellular growth and transformation. Thus, a number of
studies have focused on potential actions in neoplastic tissues. In
addition, an ever expanding repertoire of actions is being described
for these factors in neoplastic and normal AP cells, suggesting
potential activity.
TGF, previously found in, and determined to be secreted by, bovine
AP cells (184), was recently found in human pituitary somatotrophs
(185). TGF, it is worth noting, acts via EGF receptor pathways.
Evidence has been found that TGFß is synthesized in the AP (186), with TGFß1 mRNA recently localized to 80% of rat lactotrophs and lesser fractions of other AP cells (187). It has been reported that 60% of TGFß cells are lactotrophs and that treatment with estradiol in vivo decreases the number of TGFß-positive cells (188). In addition to TGFs, recent studies have provided evidence for TGF receptors in pituitary. Cells of the tumor line GH3 have receptors for TGFß as do many human pituitary adenomas (189, 190, 191).
TGF likely plays a role in regulation of lactotrophs. Transgenic
mice that are engineered to overexpress the peptide in lactotrophs have
pituitaries with increased proliferation of lactotrophs and often have
prolactinomas (192).
Although first associated with FSH secretion, TGFß can also influence secretion of PRL (193). Lactotrophs express receptors for and respond to TGFß (194), and in rat AP cells TGFß decreases PRL secretion by itself and in response to TRH (186, 195). Recently, it was found that the inhibition of PRL synthesis, secretion, and mRNA levels by TGFß declines with age and occurs at physiologically relevant concentrations (196, 197). TGFß has also been reported to stimulate labeled thymidine uptake into sheep AP cells in culture (71).
BB. TRH and prepro-TRH
The discovery of the synthesis of prepro-RH and the secretion of
TRH by AP cells added a local regulatory perspective to the
physiological actions of the products of prepro-TRH (1). Regulation of
the synthesis and processing of prepro-TRH appears to be tightly
controlled. In monolayers of cultured dissociated cells, immunoreactive
TRH and mRNA for the precursor increase slowly over 3 weeks, and the
increase is even slower in reaggregates of cells, suggesting a
cell-cell inhibition (198). Immunocytochemical and in situ
hybridization studies place the site of TRH synthesis in LH-positive
cells, an observation that is consistent with a stimulatory effect of
GnRH on TRH secretion (198). Inhibition of peptidyl amide
monooxygenase, thereby blocking processing of prepro-TRH to TRH,
increases levels of mRNA for the precursor (199). This observation is
consistent with the presence of feedback inhibition of the gene
expression by its product and the decreased rates of production of TRH,
cited above, in cell aggregates.
Aside from known actions on TSH and PRL secretion, TRH influences cell division and differentiation in the pituitary. These actions may tie in with intracellular regulation of prepro-TRH gene expression. They also might be critical in development, as distribution of cell types in the pituitary is more specific than would be expected if TRH, acting as a differentiation factor, were available solely via the hypophysial portal circulation. In vivo TRH has a mitogenic effect on thyrotrophs and somatotrophs (200). In fetal rat pituitary cells in vitro it has been shown that TRH influences the differentiation of thyrotrophs, gonadotrophs, and lactotrophs (201).
CC. Urocortin
This peptide would appear to be a likely regulator of ACTH
secretion. It is synthesized in abundance in human pituitary cells
(primarily somatotrophs) and adenomas (202), and recent work has
confirmed that it is more potent than CRH in stimulating ACTH secretion
by AP cells (203, 204). Given its distribution and potency, retention
within the cells in which it is synthesized would be physiologically
critical, lest it flood CRH-R1 receptors in the
AP. Secretion, if it occurs, would need to be tightly regulated and
this appears to be the case. One reported study in vivo
would argue against a physiological role for urocortin in a response to
stress. Immunoneutralization of urocortin during an ACTH-associated
stress had a negligible effect, whereas immunoneutralization of CRH
decreased the ACTH response to the same stress (205).
DD. Vasoactive intestinal peptide (VIP)
This peptide has long been characterized as a likely local factor
influencing function of lactotrophs (1). A number of recent
observations on the expression and actions of VIP in the pituitary are
noteworthy from the perspective of delineating the physiological role
of VIP. VIP mRNA has been localized to a subpopulation of lactotrophs
(206). Changes in osmolality in rats in vivo were found to
influence levels of pituitary PRL mRNA and inversely influence VIP mRNA
(207). Also in vivo, VIP mRNA levels in autotransplanted
pituitaries were found to be inhibited by the ensuing increase of PRL
(86). The PACAP/VIP receptor is the subject of a recent review (208).
In rat AP cells in vitro, TRH increases VIP and PRL
secretion (209).
Physiological activity of endogenous VIP. Pharmacological blockade of VIP receptors attenuates the PRL response to TRH, consistent with TRH acting, at least partially, via local production of VIP (209). Although, as noted above, VIP is apparently synthesized in lactotrophs, the actions of VIP on PRL secretion may involve other cells, as the effect on PRL of immunoneutralization of VIP in mixed populations of pituitary cells is lost in lactotroph-exclusive populations (85). In this regard it is worth noting that VIP increases secretion of galanin (85) and that VIP interacts with SP in lactotrophs (181, 182). Immunoneutralization of VIP also blocks the stimulation of PRL secretion by IGF-I (112).
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III. Intrapituitary Interactions Involving Unidentified Factors |
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TopAbstractI. IntroductionII. Factors That Are...III. Intrapituitary Interactions...IV. ConclusionReferences |
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A. Gonadotrophs
1. Gonadotrophs as source cells. Several lines of evidence
suggest that gonadotrophs are a critical source of mitogenic
and/or differentiation factors during development. The
pituitaries of gonadotroph-deficient transgenic mice (the result of
expression of diphtheria toxin in cells in which the -subunit
promoter is active) contain fewer lactotrophs than controls, implying a
role for the products of gonadotrophs in the differentiation of
lactotrophs (20). As noted earlier, the -subunit itself may be the
active factor here, but other gonadotroph-derived compounds may operate
as well. Another line of evidence comes from observations that there is
no effect of GnRH in reaggregates of 14-day-old rat lactotrophs,
corticotrophs, and somatotrophs, whereas in similar reaggregates that
also contain gonadotrophs, GnRH increases the number of lactotrophs and
corticotrophs and decreases the number of somatotrophs labeled with
radioactive thymidine (167). Similar effects are seen on PRL and GH
secretion by reaggregates of lactotrophs and somatotrophs in the
absence and presence of the gonadotroph cell line T3–1 (210).
Fragments of the POMC molecule, which appear to be secreted by
gonadotrophs during development, may be one class of mitogenic factors
(16, 169). Other, unidentified compounds are also involved. Although
the effects of gonadotrophs on lactotrophs are mimicked by POMC
fragments, the effects on somatotrophs and corticotrophs are not (16, 169).
Evidence for the existence of a factor secreted from gonadotrophs that may prevent apoptosis comes from studies in fish (101). Somatotrophs thrive in mixed cultures of all pituitary cells from tilapia. In contrast, somatotrophs cultured alone undergo apoptosis. The apoptosis can be prevented by treatment with medium conditioned by exposure to mixed cultures of AP cells or with IGF-I, which is a product of gonadotrophs in tilapia. It remains to be established whether IGF-I is the intrapituitary factor in the mixed cultures that prevents the apoptosis.
A number of other factors that influence pituitary cells have also been reported to be present or synthesized in gonadotrophs. Among those mentioned above are NO (NOS is present in gonadotrophs and its abundance is modulated by gonadal steroids, as it increases with gonadectomy), EGF, TGFß, and activin ßB. C-type natriuretic peptide (CNP) is also colocalized with LH; evidence for synthesis in the pituitary comes from the presence of CNP mRNA in extracts (211).
2. Gonadotrophs as target cells. A number of excellent recent reviews cover the subject of the control of gonadotroph function; among which are those that include discussion of local factors (Ref. 90 , for example). Among the most extensively characterized intrapituitary interactions are those involving activin and follistatin, full discussion of which will not be done here, since this area has been the intensive subject of several excellent recent reviews (including Refs. 5, 6, 7, 8, 9).
The differential distribution of morphologically distinct gonadotrophs (distribution of factors such as chromogranin and secretogranin) suggests local influences on differentiation (212). In this regard, it may be worth reexamining the potential of the so-called hypothalamic factors as intrapituitary factors. One distinction of local GnRH or TRH, as opposed to that produced by hypothalamus and distributed throughout the pituitary via the capillary beds, is the directionality of effect, which may be important in development. GnRH has recently been reported to induce differentiation of gonadotrophs in fetal pituitary cells in vitro (18). TRH, recently discovered to be secreted by pituitary cells, may also play a developmental role, as demonstrated by the effect of TRH on increasing the area of fetal rat AP immunologically identified as gonadotrophs in vitro (201).
Among the more intricate paracrine actions involving gonadotrophs is that of oxytocin-stimulated gonadotropin secretion. Since oxytocin receptor mRNA is present only in lactotrophs, the effect of oxytocin on LH secretion must involve another, as yet unidentified, intercellular interaction (165).
B. Lactotrophs
1. Lactotrophs as source cells. In addition to known factors,
there are as yet unidentified paracrine factors synthesized in
lactotrophs whose existence can be shown by the effects of lactotroph
cells being in close proximity to target cells. For example, it was
found that mean intracellular calcium and the calcium flux profiles of
lactotrophs were modulated by interactions with neighboring cells. In
doublets of dissociated cells (i.e., two adjacent cells not
completely dissociated) a greater decrease in activity of lactotrophs
was noted when the accompanying cell was another lactotroph, suggesting
the transmission of a signal from one lactotroph that dampens calcium
oscillations in neighboring lactotrophs (213).
Lactotrophs may also produce a factor that influences gonadotrophs in response to OT (see Section III.A.2 above).
An interesting observation in bullfrog pituitaries is that lactotrophs
can synthesize and secrete the -subunit of the glycoprotein hormones
(19), the effects of which are described above. It is not known whether
this observation is unique to this species or is more common.
2. Lactotrophs as target cells. As noted above, there is an
element of ambiguity with regard to local factors that influence the
proliferation or differentiation of lactotrophs. Gonadotroph-lactotroph
interactions appear to be critical, as the pituitaries of
gonadotroph-deficient transgenic mice also contain fewer lactotrophs
than those of intact mice (20). The -subunit of glycoprotein
hormones and POMC (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76) are believed to play a
role in this effect, but other factors may also be involved. GnRH was
found to increase the number of lactotrophs (168) and to induce
differentiation of lactotrophs in fetal rat cells. At least part of
this effect is due to locally produced GnRH, because in explants of
Rathke’s pouches, obtained at day 12 of gestation from rat fetuses,
treatment of explants with an antagonist of GnRH decreases the area
that stains immunocytochemically for PRL (94).
As noted above, lactotrophs secrete some factor that decreases calcium
flux in neighboring lactotrophs (213). Another unidentified factor that
influences PRL secretion may come from gonadotrophs. As determined by
the behavior of cells in reaggregate culture, T3–1 gonadotrophs
secrete some factor in response to GnRH that decreases PRL secretion
(210).
TRH was known to stimulate secretion of PRL before secretion of TRH by pituitary cells was discovered. Recent work has shed light on the potential physiological role of TRH on lactotroph function. In pituitary cells from intact male rats, TRH, but not angiotensin II—another potential locally acting agent, stimulates PRL; both peptides do so in AP cells from male rats that have been castrated and treated with estrogens (214).
C. Somatotrophs
1. Somatotrophs as source cells. Somatotrophs are arguably the
pituitary cells for which there is the most compelling evidence that
the primary systemic secretory product, in this case GH, influences the
function of the secreting cell itself. The local actions of GH in the
AP are only now being more fully elucidated. Similarly, there is new
evidence for the synthesis of bFGF in the somatotrophs of the AP (215).
Its local actions have not been elucidated but may be quite complex
(2). The intrapituitary actions of GH and other factors that originate
in somatotrophs are described in the first unit.
2. Somatotrophs as target cells. Several recent reviews (including Ref. 216) of the control of GH secretion contain valuable discussion of local factors that act within the AP. As described above, somatotrophs are target cells for intrapituitary interactions, and this extends to being a target for GH itself.
An as yet unidentified factor (possibly IGF-I) has the novel function of inhibiting apoptosis in tilapia somatotrophs, as described in Section III.A.1 above (101).
Evidence for other unidentified factors from gonadotrophs that decrease thymidine uptake in somatotrophs come from studies with reaggregate cultures of pituitary cells from 14-day-old female rats, and is also covered in Section III.A.1 above (16, 167, 169).
D. Corticotrophs
1. Corticotrophs as source cells. Recent work on potential
paracrine factors from corticotrophs appears to have focused more on
new properties of products already known to come from corticotrophs
rather than discovery of new factors. In one such study an unidentified
factor(s) from CRH-target corticotrophs, previously found to inhibit
ACTH secretion in other corticotrophs, was found to suppress levels of
POMC mRNA as well (217).
2. Corticotrophs as target cells. Recent reviews of the literature on the control of ACTH secretion include discussion of intrapituitary interactions; this includes a timely review on the inhibition of ACTH secretion (218). One unidentified factor that acts on corticotrophs is secreted from gonadotrophs (see Section III.A.1 above) that increases thymidine uptake (16, 167, 169).
As with corticotrophs as source cells, most of the recent work on corticotrophs as the target of intrapituitary factors involves characterization of the actions of already identified actors, and this is described in the first unit. An intriguing exception is the recent report of CRH biosynthesis and secretion by AP cells (219), the action of which is well known, although the significance of the discovery within the AP remains to be elucidated.
E. Thyrotrophs
1. Thyrotrophs as source cells. A number of factors, which are
known to alter the function of pituitary cells when added exogenously,
have been found to be synthesized in thyrotrophs. These have been
described above and include TGFß, SP, galanin, and the
ßB chain of activin/inhibin (21).
2. Thyrotrophs as target cells. Thyrotrophs are subject to influence in various forms by neighboring cells. Among the factors not yet identified, GnRH acts on gonadotrophs to produce a factor that induces thyrotroph differentiation (18). This factor may be TRH, because prepro-TRH mRNA has been colocalized with LH and is stimulated by GnRH (198). In vivo TRH has been found to have a mitogenic effect on thyrotrophs (200), and in fetal rat cells in vitro TRH influences differentiation of thyrotrophs as well as other cells (201). Although on this basis it is tempting to speculate that TRH from gonadotrophs plays a role in the differentiation of other pituitary cells and the proliferation of thyrotrophs, such a scenario remains to be tested.
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IV. Conclusion |
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TopAbstractI. IntroductionII. Factors That Are...III. Intrapituitary Interactions...IV. ConclusionReferences |
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Although the contribution of any given intrapituitary interaction to the overall secretion of the pituitary hormones may seem insignificant, it may be critical in terms of the integrated physiological response. Along with the innovative approaches afforded by novel technology, recognition of such roles has likely provided the basis for many of the studies and projects described above. Aside from the simple challenge of describing exchanges of information that might occur only between adjacent cells and involve hundreds of individual molecules, attention will, no doubt, be focused in the future on assessing the real impact of these interactions on the physiology of the whole organism.
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Acknowledgments |
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Footnotes |
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1 Supported by NIH Grant HD-11210, Australian Research Council Large
Grants, and Wake Forest and University of Adelaide intramural funding. 
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References |
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TopAbstractI. IntroductionII. Factors That Are...III. Intrapituitary Interactions...IV. ConclusionReferences |
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