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Modulation of Gonadotropin Levels by Peptides Acting at the Anterior Pituitary Gland

University Department of Obstetrics and Gynaecology, Christchurch School of Medicine, Christchurch, New Zealand

	Abstract

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 

I. Introduction

II. Between the Hypothalamus and the Pituitary

III. Direct Modulatory Action by Peptides

IV. Pituitary Receptors

V. Interaction of Peptides with GnRH

VI. Self-Priming by GnRH and Desensitization

A. The effect of peptides on the GnRH-primed LH response

B. The effect of peptides on the desensitized LH response to GnRH

VII. Steroids and the Ovulatory Cycle and the Effects on Peptide Characteristics

VIII. Intrapituitary Peptides

IX. Activity of Peptides in Vivo

X. Interaction Among non-GnRH Peptides

XI. Processes Other Than Secretion That Are Modulated by Peptides

XII. Summary and Conclusion

	I. Introduction

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
ENDOCRINOLOGISTS have revealed many peptides that affect LH release from pituitary cells. After GnRH was isolated, it was found to elicit LH release both in vivo and in vitro. The very potency of GnRH suggested there was little reason to suspect an important participation of other peptides in gonadotropin regulation, and it was suggested that the interactions of GnRH with ovarian steroids at the pituitary level are responsible for the final regulation of LH and FSH release (1). However, in addition to the participation of ovarian peptides such as inhibin and gonadotropin surge-attenuating factor, there remain persistent observations of various peptides expressing demonstrable LH-modulating activity. The question of the place of these peptides in the physiological schemes is frustratingly ill defined.

The careful regulation of LH and FSH are vital to full reproductive function. The secretion of the gonadotropins in the female must occur at the right time in concert with other physiological changes that occur in the reproductive axis, and the various levels that are released must be appropriate for the stage of the ovulatory cycle. It is perhaps not surprising that it is becoming apparent that the production of precise amounts of gonadotropin is achieved by the interaction of a number of components. The inclusion of several participating factors in the endocrinological scheme enables both fine tuning of signals and buffering against unsuitable stimuli. This review considers some of those peptide signals. Additionally, understanding the modulatory processes of the gonadotrope can provide information that can be generalized to other endocrine systems.

This review considers peptides that have in the past decade or so been observed to affect gonadotropin activity and often appeared to have their main derivation in the hypothalamus. Their possible function in LH or FSH control is noted in this review. The peptides include endothelin, galanin, neuropeptide Y (NPY), oxytocin, pituitary polyadenylate cyclase-activating polypeptide (PACAP), and substance P, and also C-type natriuretic peptide (CNP), epidermal growth factor (EGF), interleukin (IL)-6, nerve growth factor (NGF), gastrin-releasing peptide and opioids, and, less certainly, neurotensin and vasoactive intestinal polypeptide (VIP). None has yet been ascribed an importance equal to the primacy bestowed on GnRH. However, the ability of these compounds to influence LH release in the absence and/or presence of GnRH (Fig. 1) suggests that the physiological regulation of gonadotropins is a result of interaction of many peptidic factors. The manner in which the peptides interact with GnRH and among themselves, the molecular mechanisms that possibly underlie the processes, and how so many factors are integrated into a physiologically functional system pose fascinating questions.

View larger version (16K): [in this window] [in a new window]   Figure 1. Five processes by which peptide can potentially modify LH secretion from gonadotropes, with selected examples of activities that are further discussed in the text. The action of the peptide is represented by the black arrows. A, Peptide is transported from the hypothalamus and directly acts on the gonadotrope, e.g., oxytocin (70 ). B, Interaction of peptide from the hypothalamus with GnRH, e.g., NPY (58 ). C, Peptide elicits release of another substance that acts on the gonadotrope and so produces a paracrine mechanism of action, e.g., PACAP stimulates IL-6 release from folliculo-stellate cells (303 ). D, Peptide is released from a cell within the pituitary, e.g., galanin from lactotropes (221 226 ). E, An autocrine process utilizing peptide synthesized within the gonadotrope, e.g., substance P (233 ).

	II. Between the Hypothalamus and the Pituitary

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

Most of these peptides considered in this review have been detected in the median eminence before departure from the hypothalamic region. Observations of localization or measurement in the median eminence region of galanin (10), NPY in rats (11, 12) and in lambs (13), neurotensin (14), oxytocin (15, 16), PACAP in rats (17, 18), sheep (19), humans and primates (20), substance P (21, 22), and VIP (18, 23) have been reported.

The presence of the peptides in portal blood (Table 1), in transport to the anterior pituitary gland subsequent to their release from the median eminence, is a crucial, although not a definitive, observation that is necessary before it is possible to suggest a hypophysiotropic activity of the peptides (Fig. 1, A–C). Unfortunately, the type of cell being targeted by portal blood peptides is not always clear, and many nongonadotrope-related activities are also possible. It is a matter of note that the mechanism or capacity of release from the median eminence may be species specific (24). In sheep the portal blood system does not seem to transport several of these peptides, including galanin, neurotensin, NPY, substance P, and VIP, at levels above those found in the periphery, suggesting secretion from the hypothalamus has not occurred. Changes to levels of peptides in the portal blood have been observed during the estrous cycle of rats, and it is noteworthy that concentrations, when variations have been detected, are almost always highest at times associated with high LH levels. Both galanin (10) and NPY (25) are highest at proestrus, and in rabbits NPY is released from the hypothalamus in conditions producing an LH surge (26). Oxytocin also has a proestrous peak (27), and in horses an oxytocin rise in portal blood, produced endogenously by response to sexual stimulation or by exogenous administration, is linked with a rise in LH (28). Raised levels of peptide in portal blood at times linked to when LH levels are elevated suggest that at least one physiological role of these peptides is gonadotropin regulation. Interestingly, in view of indications that ß-endorphin plays an inhibitory modulatory role in gonadotropin regulation (see below, Sections III andV), ß-endorphin levels in portal blood were highest on the morning of proestrus before the LH surge and lower at later times, suggesting an inverse relationship between ß-endorphin and GnRH secretion (29, 30), although a stimulatory component of ß-endorphin action has also been noted (31).

	III. Direct Modulatory Action by Peptides

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
More direct evidence for a role in gonadotropin regulation at the pituitary is provided by observations of an effect by a peptide on gonadotropin release from pituitary cells in vitro (Fig. 1, A–E) (Table 1). A significant body of information has also been obtained using T3–1 cells (Fig. 1, A, B, D, and E), a GnRH-responsive cell line of the gonadotrope lineage derived by targeted oncogenesis in transgenic mice (42, 43). These cells are immortalized apparently at an arrested stage of development (44) and do not secrete LH. The characteristics of the cells are consistent with appearance of -subunit before LH-ß in ontogenic development (42, 43). Nevertheless, the intracellular events elicited in T3–1 cells in response to endocrine stimulation seem comparable to those of mature gonadotropes (43, 45, 46).

It is of some interest to consider the mechanisms invoked by the peptides in their LH modulatory activity in the cases in which they have been investigated. First, the differences or similarities among mechanisms activated by separate peptides, and the corresponding effects on the various aspects of LH control, can throw some light on which pathways are important for the different processes and steps that constitute the stimulus-secretion cascade. It is possible some peptides stimulate pathways that are redundant, and it is possible some pathways have specific and unique roles. Second, the potential for cross-talk and convergence of pathways will be illuminated by detailed knowledge of peptide-activated mechanisms so that possible interactions can be considered and synergistic augmentation or modulatory inhibition can be revealed.

Endothelin elicits gonadotropin release from pituitary cells in vitro with high efficacy (47) via ET_A receptors (48, 49) utilizing the same postreceptor transduction pathway as GnRH, i.e., increased levels of inositol 1,4,5-triphophosphate (IP₃) and diacyl glycerol (DAG) and a subsequent increase in intracellular [Ca⁺⁺]. The magnitude of the [Ca⁺⁺]_i responses triggered by endothelin and GnRH are similar (50). Endothelin-1 caused ion currents in isolated gonadotropes similar to those induced by GnRH and elicited LH release (51). Endothelin can possibly selectively stimulate LH or FSH by acting via different G proteins and activate separate secretion-coupled processes (52). The LH response to endothelin is more rapidly and profoundly desensitized than that to GnRH (50). There is therefore a relatively reduced sustained LH response elicited by endothelin. Thus LH-regulating peptides can have effects that do not mimic GnRH. Recent studies suggest the absence of the GnRH receptor intracytoplasmic carboxy-terminal tail and sequences of the third intracytoplasmic loop provide the molecular basis for some of the characteristics of GnRH as compared with other G protein-coupled receptors (GPCRs), presumably including endothelin receptors, as they relate to desensitization (53).

Galanin has been observed to increase LH secretion from rat pituitary cells in vitro (10, 54). Results derived from studies of galanin mRNA suggest that galanin correlates more tightly with LH than FSH serum levels (55). Galanin, additionally, enhances GnRH binding to pituitary tissue membranes (56). On the other hand, galanin has been observed to inhibit GnRH-stimulated -subunit release and inhibited intracellular cAMP accumulation in T3–1 cells (57). Isolated anterior pituitary cells from male rats did not respond to exposure to galanin (51). A series of observations such as these with galanin, which report apparently contradictory effects, is not unusual in this area of peptidic gonadotropin control. It is probable that although galanin has been observed to have both stimulatory (10, 54, 56) and inhibitory effects (57), the disparate sequelae are an accurate reflection of the activities in vivo at particular endocrinological circumstances.

It is particularly enlightening when assessing the possible role of any peptide in gonadotropin regulation to consider the case of NPY. A lack of effect of NPY on LH release in vitro has been reported in some studies employing rat cells (58, 59) and in others on sheep cells (60). No ion currents similar to those induced by GnRH were elicited by NPY on anterior pituitary cells from male rats (51). In contrast a clear stimulatory activity was observed in other studies employing rat tissue (61, 62, 63) and macaque pituitaries (64). Furthermore, in certain endocrinological circumstances, a suppressive effect of NPY on GnRH-stimulated gonadotrope responses has been reported (65, 66). Thus again, a particular peptide can display a series of activities that presumably reflects physiological mechanisms (Fig. 2). There are apparently no studies on the intracellular pathways recruited to mediate the effect of NPY on basal LH release, although there are some studies that investigate the effect of NPY on GnRH-stimulated LH release (see below, Section V). NPY has been reported to stimulate FSH release from the anterior pituitary (62), but an effect has not been observed in all studies (59, 63). NPY induced secretion of both LH and FSH from anterior pituitary tissue pieces from rabbits (67).

View larger version (26K): [in this window] [in a new window]   Figure 2. Examples of distinct effects on LH secretion of a single peptide (NPY). 1) Direct stimulation (left panel): When dispersed anterior pituitary cells were perifused with NPY there was an increase in gonadotropin release (62 ); 2) No effect (middle panel, basal): NPY has no direct effect on LH release from cultured anterior pituitary cells (58 ); 3) Augmentation of GnRH-stimulation (middle panel, LHRH): Cultured anterior pituitary cells were incubated for 3 h. LH release induced by GnRH plus NPY was greater than the additive effects of the two peptides separately (58 ); 4) Suppression of stimulation (right panel). In a perifusion system metestrous anterior pituitary cells exhibited progesterone-augmented GnRH-stimulated LH secretion (bar 6: GnRH + P4). Concurrent treatment with NPY caused reversal of the progesterone augmentation (bar 8: GnRH + P4 + NPY) (66 ). [Reproduced with permission from J. K. McDonald et al.: Proc Natl Acad Sci USA 82:561–564, 1985 (62 ); W. R. Crowley et al.: Endocrinology 120:941–945, 1987 (58 ) © The Endocrine Society; Adapted with permission from K. L. Knox et al.: Endocrinology 136:187–195, 1995 (66 ) © The Endocrine Society.]

PACAP has been observed to stimulate LH release from anterior pituitary gland cells (74, 75, 76). PACAP stimulates an accumulation of intracellular cAMP in pituitary gonadotrope cells and enhances LH release (77). However, many of the PACAP-induced alterations of intracellular metabolism in gonadotropes occur by enzyme systems involving mediators other than protein kinase A (PKA) and cAMP (75). In the rat pituitary, PACAP, acting via a type I receptor (78), induces an increase in intracellular [Ca⁺⁺] of gonadotropes (51, 77, 79), an effect that occurs independently of cAMP increase or of PKA activation (80), probably incorporating a role of PLC (81, 82). The stimulatory activity of PACAP on LH and -subunit secretion depends, at least in part, on activation of PKC (83). IPs (to mobilize Ca⁺⁺ from intracellular Ca⁺⁺ stores after activation of PLC) and possibly DAG may be involved in stimulation of LH release (81, 84) via a G protein-dependent pathway (82) but the process is independent of a mechanism utilizing extracellular calcium. There is thus activation by PACAP in gonadotropes and T3–1 cells of two intracellular pathways that were traditionally considered distinct (one activating PLC and one activating adenyl cyclase) (81). However, there is molecular interaction and cross-talk between them (78, 85), thereby providing for complex modulatory capabilities. Thus there are metabolic options available to LH-regulating peptides that are not necessarily invoked by GnRH. PACAP has also been observed to suppress FSH mRNA levels and lengthen LHß mRNA molecule. The cAMP-PKA second messenger pathway, although it does not appear to have a central role in PACAP-induced LH secretion, might be involved in differential regulation of gonadotropin subunit gene expression (74). Stimulation of cAMP production has also been observed in sheep glands (86) via type I receptor (87). However, it seems that PACAP has no direct effect on the anterior pituitary gland in regulation of LH in the sheep, although a modest increase in FSH secretion from sheep pituitary cells was observed at high PACAP doses (88).

Substance P had no effect on pituitary cells from estrogen-treated ovariectomized rats (89). However, the importance of the appropriate endocrine environment to enable expression of optimal substance P activity is suggested by the observation that the stimulated LH secretory response to substance P by pituitaries from females rats was bigger than by pituitaries from males (90, 91). Additionally, it has been suggested that results of investigations depended also on the type of cell preparation, so that cells kept in suspension overnight were not responsive in contrast to cells attached to culture wells (91). The stimulatory effect of substance P is also observed on prepubertal porcine cells (92).

Some compounds that are usually studied in other contexts have also been observed to affect LH. These include CRF, a factor more usually associated with corticotrope cell type, which has been reported to reduce LH release from rat cells (93) and human fetal pituitaries (94) in vitro. Also opioids, more traditionally assumed to affect gonadotropin release by inhibitory effects on GnRH release in the hypothalamus, have been reported to directly affect LH release at the pituitary (93). ß-Endorphin stimulated LH release from anterior pituitary gland tissue in vitro in the presence of high estrogen. On the other hand, ß-endorphin was inhibitory when progesterone was added to the incubation mixture (31). The observations led to speculation that ß-endorphin acts to potentiate the production of the LH surge when estrogen levels are high, and in conjunction with progesterone, ß-endorphin participates in the termination of the midcycle surge of LH. Additionally the secretion of ß-endorphin from pituitary cells has been observed, indicating that hypothalamic ß-endorphin is not necessarily the source of all ß- endorphin that impinges on the gonadotropes. The level of secretion was modulated by steroids, revealing potential for a regulated intrapituitary paracrine role. Estradiol enhanced the release of ß-endorphin, which could be further augmented by progesterone (31). Opioids were found to differentially modify the release of LH depending on opioid receptor subtype that was activated. Spontaneous LH release was inhibited by opioids acting via µ- and -receptors, and GnRH-stimulated LH release was inhibited by µ- and -receptors. It was suggested that the neurointermediate lobe, too, might be a physiological source of these compounds (95).

A further influence on gonadotropes can be exerted by EGF, which directly stimulates LH release in vitro, apparently through a mechanism involving phospholipase A₂ (PLA₂) and arachidonic acid (96). Furthermore, EGF has been revealed to have potential to modify the estrogen-mediated secretion of LH by increasing responsiveness to the steroid (97). Also, gastrin-releasing peptide has been observed to stimulate LH release from anterior pituitary cells in vitro (98).

Therefore, there is a significant body of observations that points to gonadotropin secretion being regulated, in part, by peptides acting at the pituitary. The studies in vitro are able to isolate the pituitary effects from those that might occur within the hypothalamus. The number of peptides observed to have an effect in this regard raises the question of whether all or some have physiological activity and how they are integrated into the endocrinological events that occur in vivo.

	IV. Pituitary Receptors

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
For such peptides to act at the pituitary requires the presence of receptors. In fact, it is often assumed that the presence of receptors implies that the corresponding peptide exerts a physiological influence on the cell (Fig. 1, A–E). In the pituitary, high-affinity receptors have been found for many of these peptides, although whether receptors are on gonadotropes has not always been determined. However, the receptors have sometimes been detected, directly or by measurement of a receptor-mediated activity, on T3–1 cells, a gonadotrope-derived cell line, providing strong inferential evidence that mature gonadotropes would be similarly endowed (Fig. 1, A, B, D, and E). If the receptor to an LH-modulating peptide is not on gonadotropes, but present in the anterior pituitary gland, then a paracrine activity is suggested.

Direct evidence for endothelin-1 binding sites in the anterior pituitary gland has been obtained using I¹²⁵ binding to identify ET_A sites on pituitary tissue (49), and endothelin-stimulated responses have been detected in T3–1 cells (99). Endothelin receptors have been detected also in human pituitary tissue (100). It took some time for specific NPY sites to be confirmed on the anterior pituitary gland. This delay was apparently because NPY has a small number of high-affinity sites that are dominated by a greater number of low-affinity sites and are therefore difficult to detect (56). Oxytocin has been observed to bind to anterior pituitary gland sites, and binding is increased by estrogen (101), and the level of oxytocin receptor mRNA was increased by estrogen treatment (102). Although positive identification of oxytocin receptors on mature gonadotropes is still lacking, oxytocin has been observed to stimulate [Ca⁺⁺]_i increase in T3–1 cells (73) and also elicit LH release in isolated gonadotropes (51).

PACAP has been observed to bind with high affinity to pituitary membranes (103, 104) and to gonadotropes, as well as to other hormone-containing cell types and folliculo-stellate cells (104). A cDNA encoding a receptor for PACAP was identified by PCR of rat pituitary cDNA (105). PACAP stimulates cAMP and IP production in T3–1 cells (81) and pituitary tissue via type I receptors. It has been found that T3–1 cells express mRNA for PACAP/VIP receptor (PVR)1 (and to a lesser extent PVR3) but not PVR2 (106).

Substance P has binding sites on the anterior pituitary gland. Numbers of substance P receptors vary during the estrous cycle, being inversely related to GnRH binding site population changes (107). High-affinity sites have also been detected in human tissue (108). In accord with the observation that EGF affects LH secretion, EGF receptors have been detected in the rat and human pituitaries (109, 110). The level of EGF receptors is modulated by the changing conditions of the estrous cycle. Peak expression of EGF receptors by gonadotropes occurs at diestrus and proestrus, suggesting EGF might be involved in preparation of the LH surge (111). Opioid receptors have been detected in the anterior pituitary gland of cows (112), although they are more prominent in the posterior pituitary of mammals (112, 113, 114), and an opioid-mediated regulation of gonadotropin activity has been observed in rat cells (93).

One problem in answering the question of whether peptide receptors are on gonadotropes is the variation of receptor number, possibly to below a detectable level, with endocrine environment and cycle stage [e.g., for oxytocin (115, 116)]. Additionally the question of hidden sites, awaiting unmasking by a second peptide (EGF), has been noted with respect to GnRH binding sites (117), and it is possible that a similar phenomenon pertains to other peptide receptors also. Thus, both an increase in real number by up-regulation and by the unmasking of nonfunctioning receptors can occur, as well as a possible modulation of affinity as observed for GnRH receptors under the influence of NPY (56). Conversely, reduction in GnRH receptors can be effected by opioids (118). Thus, certain experimental conditions must be fulfilled before receptors will be optimally observed.

However, it can be established that a particular peptide has LH-regulating activity without knowing the precise mechanism. From this perspective it does not matter, except as a detail, whether the process of peptide action on gonadotrope is endocrine or paracrine.

	V. Interaction of Peptides with GnRH

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
In addition to, or perhaps instead of, direct activity on secretion, the peptides might act on pituitary cells in conjunction with GnRH (Fig. 1B) (Table 1). On the basis of this concept, full production of the LH surge in proestrus would require participation of both GnRH and other peptides, and for convergence or cross-talk of intracellular processes stimulated by these other peptides with GnRH-stimulated pathways.

GnRH receptor activation recruits a variety of pathways for different aspects of the stimulated response (119, 120, 121). After GnRH binding to its specific, seven-transmembrane domain receptor (122, 123, 124), there is consequent alteration of an associated heterotrimeric G protein (125, 126). Two smaller units are separated from the large -subunit that participates in activation of PLC or adenyl cyclase. G protein-mediated activation of PLC results in hydrolysis of inositol 4,5-bisphosphate with generation of IP₃ and DAG (127, 128). DAG remains bound at the membrane. IP₃ is soluble in the cytoplasm and binds to receptor on the endoplasmic reticulum and induces release of Ca⁺⁺ from the intracytoplasmic stores. This, together with Ca⁺⁺, which enters via membrane channels, results in an increase in [Ca⁺⁺] (129, 130, 131, 132). The Ca⁺⁺ interacts with PKC, facilitating transportation and attachment to the membrane, where PKC associates with DAG to convert PKC to its active state. Receptor activation of phospholipase A₂ (PLA₂) will produce arachidonic acid (133, 134), and activation of phospholipase D will result in the formation of phosphatidic acid (135). Activation by G protein of adenyl cyclase results in production of cAMP and subsequent activation of PKA (136, 137, 138, 139).

Interaction with any of these processes and compounds by processes activated by the peptides being considered could therefore produce an influence on GnRH-stimulated activities (Fig. 3). Many of the groups of compounds recruited to propagate the signal exist as isoforms or as closely related subtypes. Thus there are opportunities for specific and selective modulation by peptides that can interact with certain of the enzymes that are incorporated into the signaling process. For example, types of adenyl cyclases are dynamically integrated according to physiological state (140), and so modulation can be confined to particular circumstances. Similarly, protein kinase C isoforms in gonadotropes are potentially activated in series by metabolites that become involved in the intracellular processes along points of a time-dependent sequence after activation of receptor. Thus, the subspecies of enzyme, such as Ca⁺⁺-dependent and Ca⁺⁺-independent forms of PKC, can be coordinated with the various physiological tasks undertaken by the gonadotrope (141), and peptide modulation can be targeted to a specific process. Multiple PLC isozymes have also been identified, and they too have distinct characteristics of activation (142, 143, 144).

View larger version (15K): [in this window] [in a new window]   Figure 3. Potential points of interaction between modulating peptides and GnRH. A simplified schematic diagram of receptor activation and the ensuing intracellular events. Peptides that have been observed to potentially interact with or affect a particular metabolic entity are listed.

There is also potential coupling of receptors to dual transduction pathways (163, 164). One type of dual signaling is exhibited by the subfamily of GPCRs that includes PACAP, CRF, and VIP. In these cases, receptors stimulate both adenyl cyclase and PLC. A second group of receptors mediate inhibition of adenyl cyclase and stimulate PLC. GnRH is also known to activate both the PKA and the PKC pathways in gonadotropes, although the physiological conditions applying to each are still uncertain.

Thus, interactions of peptide with GnRH can be a complex but finely targeted, specifically restricted, coordinated process. Stimulation by GnRH of a process such as acute LH secretion, which apparently involves IP₃ increases but not stimulation of cAMP, would nevertheless, in theory, be able to interact by cross-talk with a peptide that preferentially activated adenyl cyclase, thereby making the interaction between GnRH and the other peptide sensitive to cAMP-modulating factors. On this basis it makes it very problematic to predict the effect of a peptide, an exercise made more difficult by a paucity of information on intracellular processes activated by the peptides in various and specific circumstances at the gonadotrope. Some information is available, as discussed above (Section III). Interaction of peptides with GnRH can be not only with GnRH transported from the hypothalamus but also with GnRH that is produced within the gland (165, 166).

Additionally, the interaction of peptides with GnRH can be via modification of characteristics of the GnRH receptor. The presence of masked GnRH receptors provides potential for peptides, by unmasking the GnRH receptors, to alter responsiveness of the tissue to GnRH. A mechanism of unmasking, involving calcium/calmodulin protein kinase, has been proposed (167). An alteration by NPY of GnRH receptor has been observed (see below).

The responses to endothelin and GnRH are additive at submaximal doses, but not at maximal doses, in accord with the observation that these two peptides share intracellular pathways. In addition, more complex interactions have been distinguished when sequential exposure occurred. Endothelin-stimulated cells can show facilitated or attenuated [Ca⁺⁺]_i and LH responses to GnRH according to the duration of and time since endothelin exposure (50). There is, therefore, another example of the different responses that can occur depending on details of the hormonal circumstances.

The augmentation by galanin of the ability of GnRH to stimulate LH release (10, 54) was apparently at least partly by enhanced binding of GnRH (56). GnRH-stimulated FSH secretion was augmented by NPY (63). In addition, LH secretion was modified. The sensitivity of the anterior pituitary gland to NPY enhancement of GnRH-stimulated LH release is increased by the conditions of proestrus (168). The facilitatory effect of NPY on GnRH-stimulated LH release is mediated by PKC (169). NPY enhanced the affinity of GnRH binding independent of any effect on maximal receptor number (56) by inducing an allosteric alteration in GnRH receptor. There was a subsequent augmented influx of extracellular Ca⁺⁺ followed by enhanced release of LH (170). In addition, it appears that NPY, via specific receptors, is able to induce unmasking of cryptic GnRH receptors in male rats. The process is dependent on both GTP-binding proteins and calcium calmodulin-dependent kinase (171). Also, NPY blocked the GnRH-induced rise in - and ß-FSH mRNA in rats ovariectomized and given estrogen in the absence of progesterone (172). The suppressive effect of NPY on GnRH-stimulated [Ca⁺⁺ ]_i signals (and thus on LH release) occurs via activation of a pertussis-sensitive G protein (65). However, in macaque pituitary preparations, NPY did not affect GnRH-stimulated LH secretion (64).

Oxytocin has been observed to augment GnRH-stimulated LH release both in vivo (173) and in vitro (174). Although cAMP by itself enhances GnRH-stimulated LH release (see below, Section VI), the augmentation by oxytocin of GnRH-stimulated LH release is inhibited by cAMP (175). This finding can be noted alongside the observations, in both rat and human myometrial tissues, that cAMP analogs suppress oxytocin-stimulated increases in [Ca⁺⁺]_i levels and phosphoinositide turnover (176, 177, 178, 179), indicating that oxytocin and GnRH at the gonadotrope possibly interact by utilizing a process already identified in another tissue.

PACAP interacted synergistically with GnRH in stimulating both LH and FSH (75) and is able to amplify GnRH-stimulated IP accumulation (81). On the other hand, GnRH pretreatment of T3–1 cells diminished the effect of PACAP on stimulation of [Ca⁺⁺]_i to an extent comparable to the effect on subsequent GnRH stimulation (180). Conversely, GnRH inhibits PACAP-stimulated cAMP production in T3–1 cells by a Ca⁺⁺-independent process. The effect may be mediated by PKC (78). The fascinating possibility has been proposed that pulsatile GnRH thereby forces a pulsatile response pattern on PACAP-stimulated cAMP to optimize PACAP effects on gonadotropes (78). Coordinated regulation of the -subunit gene by PACAP and GnRH possibly involves a cAMP response element (181).

Substance P was found to have an inhibitory effect on progesterone-stimulated GnRH-induced LH release. On the other hand, no effect was seen on estrogen-inhibited GnRH-induced LH release (90). In vitro perifusion of rat anterior pituitary cells with substance P demonstrated an inhibition of GnRH-stimulated LH release via a NK1 receptor (182). In another investigation of rat cells, substance P exhibited an inverted U shaped dose response; at between 1–100 nM, substance P augmented 100 nM GnRH-stimulated release and at 10 µM, substance P was inhibitory (54). In cultured human anterior pituitary gland cells, substance P inhibited GnRH-stimulated LH secretion but did not affect GnRH-stimulated FSH secretion (108). In contrast, on cells from prepubertal female pigs substance P potentiated GnRH-stimulated LH release (92), indicating an apparent species-related difference.

Other peptides that interact with GnRH include EGF, which is able to unmask previously nonbinding receptors (117), and opioids, which suppress GnRH-stimulated LH release from anterior pituitary tissue from rats (54, 95).

The potential for convergence of pathways activated by these peptides with GnRH-stimulated pathways is therefore established. The extent to which such occurs is yet to be resolved. However, the evolution of experimental methodologies and the established biological paradigms for study indicate that progress in the investigations of such intriguing problems will proceed rapidly. It is necessary that such interactions among peptides, including GnRH, be recognized to fully understand the endocrinology and so provide therapies for modulating fertility.

	VI. Self-Priming by GnRH and Desensitization

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
Some further speculation on the manner in which peptides alter GnRH activity can be based on the phenomenon by which GnRH interacts with itself and enhances its own activity by the self-priming process. If GnRH utilizes certain pathways to augment its own activity, then it is plausible that at least some of the peptides will activate processes that will interact with those same intracellular pathways and so augment GnRH-stimulated gonadotropin release by heterologous enhancement, as alluded to in the previous section. It is therefore relevant to briefly consider the manner in which GnRH modulates its own activity.

Of some interest is the evidence pointing to involvement of cAMP (183) and PKA (184) in the self-priming process in view of the absence of prominent roles in acute LH release (183, 185). Other kinases, tyrosine kinase (186), MAP kinase (187), and PKC (188, 189), have also been implicated. So too have the lipases, PLC (190) and PLA₂ (189). The self-priming phenomenon is apparently RNA and protein synthesis dependent (189, 191, 192, 193), and an estrogenized environment is required (194, 195, 196).

GnRH priming apparently results at least partly from facilitated coupling of GnRH receptor to its effector, PLC, with consequent increased IP production and markedly facilitated mobilization of Ca⁺⁺ stores (197). It has been suggested that the induction (as opposed to expression) of priming is dependent on a PKC-mediated (188) MAP kinase activation (187). After a protein synthesis-dependent step (189), PLA₂ is activated (189). The synthesized protein is probably neither the GnRH receptor nor LH (192, 198, 199) and is possibly PLA₂-activating protein or PLA₂ itself (189). Later production of arachidonic acid (or metabolites) is probably involved in facilitation of stimulus-secretion coupling, which is characteristic of the self-priming phenomenon (189). Thus, there seems to be facilitation of the response to GnRH at both an early stage in the signal transduction pathway and also at a later step in stimulus-secretion coupling (200).

Another mechanism within the priming process involves GnRH-receptor-mediated activation of adenyl cyclase, increase in cAMP, and activation of PKA with subsequent progesterone-independent transcriptional activation of progesterone receptor (184, 201), and also stimulation of protein synthesis (183). There is consequent augmentation of LH release (184).

A. The effect of peptides on the GnRH-primed LH response
It is also of some mystery that few of the studies of peptides have considered the effects on GnRH self-primed responses. A different effect of peptide on a second or subsequent pulse of GnRH from that observed on the first pulse would have significance in directing attention to the phase in which the peptide might be most physiologically important.

B. The effect of peptides on the desensitized LH response to GnRH
Additionally, the desensitization process (202, 203), which occurs after prolonged exposure of GPCRs to agonist, is potentially available for modulation by peptides. Although GnRH receptor is a GPCR, it is believed that the absent C-terminal cytoplasmic portion and also third intracellular loop sequences of the GnRH receptor confer particular properties on the receptor (53). It has been suggested that the process of desensitization for GnRH is different from that which occurs in other GPCRs in which phosphorylations of certain amino acids appear to be important steps before uncoupling from the receptor’s effector system (204, 205). Desensitization is a process involving G proteins (206, 207). GnRH pretreatment seems to impair the efficiency with which IP₃ mobilizes Ca⁺⁺ from intracellular stores but does not induce uncoupling of GnRH receptors from their immediate effector system (180, 208). Receptor loss or decreased receptor binding might also occur (53, 209, 210). Whether other peptides can modify the GnRH receptor desensitization is at this stage unanswered. However, it has been suggested that desensitization and recovery can occur within an endogenous GnRH pulse and interpulse times (211) and that rapid GnRH-induced desensitization occurs via a postreceptor process (208). Therefore, peptide-mediated modification of GnRH activity via this mechanism would need to be targeted appropriately.

Therefore, by modifying the pathways of self-priming and desensitization, non-GnRH peptides could be able to modulate the response of gonadotropes to GnRH. Additionally, the peptides under consideration can themselves be desensitized by the more well recognized processes. Apparently, however, desensitization might occur with a different time profile from GnRH (e.g., for oxytocin (73) and endothelin (50)). Desensitization to PACAP, induced by preincubation with PACAP, has been observed for GH in rat cells (212) and for LH in sheep cells (87).

It is possible that there is an array of processes that are occurring sequentially or concurrently. This can take the form, for instance, of receptors to some peptides being desensitized as others are being up-regulated, and of peptide-mediated transduction pathways engaging in cross-talk with GnRH-regulated intracellular enzymic systems, when all the while the processes can be modulated in part by steroids.

	VII. Steroids and the Ovulatory Cycle and the Effects on Peptide Characteristics

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
One group of compounds with well known modulatory influence, on peptide activity as well as on GnRH, is steroids. The effect of steroids in vivo can be inferred from effects during physiological or experimental changes in endocrine environment. In addition, changes to the LH-regulating activities of the peptides have been induced in vitro by altering steroid environment.

Endothelin-induced secretory responses of cells of female rats were dependent on the in vitro endocrine environment such that estrogen- and progesterone-mediated modulatory influences that reduced augmented responses to perifusion of endothelin were observed (213). In optimum conditions, endothelin elicited responses comparable to those that occurred in response to GnRH.

NPY augmented GnRH-stimulated LH release in vitro from proestrous pituitaries and not from metestrous pituitaries (168), progesterone apparently mediating the reduction of augmentory activity. In fact, the endocrinological environment associated with metestrus promoted a suppressive effect of NPY, suggesting that NPY contributes to constraining the production of the LH surge to the physiologically appropriate time (66). The corresponding effect is seen in vivo, too, where NPY enhancement of GnRH-induced LH release occurred only under conditions leading to an LH surge (214). Other in vitro results suggest that estrogen alone can maximize NPY potentiation of GnRH-induced LH release, and that progesterone is not mandatory (63). Additionally, NPY potentiated GnRH-stimulated FSH release (63). NPY stimulated LH and also FSH secretion from pituitaries from intact rabbits, but only transiently from pituitaries from ovariectomized animals, revealing a determining role for ovarian factors in this species too (67).

The stimulatory capacity of oxytocin is enhanced by exposure of cells in vitro to estradiol and inhibited by preincubation with progesterone (69). In vivo oxytocin was observed to be active in an estrogenic environment and advanced the LH surge in rats when administered at proestrus (215) and in humans when oxytocin was infused in the late follicular phase (216).

Not all of the peptides have received equally detailed attention with regard to steroid effects. However, the effects on peptides’ efficacy that have been observed suggest that all will be controlled in some manner by steroids. The corollary of such speculation is that negative results regarding stimulation of LH secretion by peptide will sometimes reflect the endocrinological conditions of study and not an inherent inertness of the peptide (Fig. 2).

	VIII. Intrapituitary Peptides

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
A number of the peptides or peptide mRNAs have been detected in the anterior pituitary gland (217, 218). This suggests that the hypothalamus is not the only source of peptides that modulate gonadotrope activity (Fig. 1, D and E). Changes in levels of pituitary peptide or peptide mRNA in concert with altered levels of the reproductive steroids have been reported in some cases. However, on a cautionary note, there have been observations indicating that locally produced peptides do not necessarily participate in paracrine regulation of hormone release (219).

Endothelin-3 has been reported to be the most abundant endothelin in the pituitary gland in rats (220) and in humans (100). However, endothelin-3 bound with less affinity than endothelin-1 to ET_A receptor subtype although it is ET_A receptors that mediate the effect of endothelins on gonadotrope secretion. On the other hand, endothelin-1 is the predominant form of endothelin in the hypothalamus. Thus the hypothalamus may be the source of physiologically active endothelin targeted to gonadotropes. Nevertheless, some stimulatory activity of endothelin-3 on LH and FSH has been observed (49, 52). Endothelin mRNA has been detected also in human pituitary tissue (100). Also pituitary galanin mRNA has been observed in pituitaries and is modulated by steroids. Estrogen-induced increases in galanin mRNA in immature rats were enhanced by progesterone (55). Levels of galanin mRNA and also galanin peptide immunoreactivity are potently increased by estrogen (221, 222, 223), and galanin release from anterior pituitary cells (221) and from MTW-10 cells (224) is increased in the presence of estrogen. Galanin appears to be localized in lactotropes in estrogenized pituitaries (225, 226). NPY and NPY mRNA, too, have been detected in the pituitary of rats (227) and NPY mRNA in the pituitary of humans (228). NPY and NPY mRNA content of the pituitary increased after ovariectomy, and the changes were reversed with estrogen replacement (227). Oxytocin was detected in lactotropes of rats (229), and so one component of LH regulation by oxytocin might include intrapituitary activity involving lactotropes. PACAP has also been observed in the anterior pituitary gland in gonadotropes of female rats (230, 231). The highest amounts of PACAP mRNA were present during the LH surge (230). PACAP-containing nerve fibers were identified immunohistochemically in the anterior pituitary gland of male rats, but PACAP was not observed in the secretory pituitary cells in those animals (17), although in another study PACAP-containing gonadotropes were detected (231). PACAP was not detected in the anterior pituitary gland of sheep (19).

Substance P is localized in the anterior pituitary gland of guinea-pigs (232) and rats including in identified gonadotropes (233), and substance P mRNA has been detected in the pituitary of humans (228). Substance P is secreted by anterior pituitary gland tissue in vitro (234, 235). Modulation of substance P by steroids has been demonstrated, and it seems that androgens stimulate and estrogens inhibit the accumulation of substance P in anterior pituitary gland tissue (236, 237), and substance P content is at least double in males compared with females (238). Interestingly, estrogen decreased substance P mRNA levels, but affected substance P peptide levels to a lesser extent (21). Ovariectomy of rats produced a rise in substance P (227). Additionally, the mRNA substance P precursor is affected by estrogen (21, 227). The effect of estrogen on pituitary substance P does not parallel that on substance P in the hypothalamus. Testosterone increased pituitary substance P mRNA, although not of protein (237). However, there is a 10-fold difference in mRNA between males and females, cautioning again that there appear to be distinct controls on the different stages of peptide metabolism. Estrogen also regulated substance P content of the anterior pituitary of cynomolgus monkeys such that estradiol benzoate administration depleted anterior pituitary content, perhaps thereby suggesting that physiologically there is in estrogen-rich conditions a lessening of the inhibitory effects of substance P on GnRH-induced LH release (239).

In addition, GRP-like immunoreactivity has been detected in gonadotropes, suggesting a direct action in regulation of gonadotropins (98). GRP has been identified in other cell types also and therefore could be active in a paracrine mechanism (219, 240). It has been suggested that intrapituitary opioids from corticotropes mediate the effect of CRF in reducing LH secretion (93, 94). Basal release of LH in vitro is increased in the presence of naltrexone or ß-endorphin antiserum. It is possible that secretion of endogenous opioids exerts a tonic physiological suppression on gonadotrope secretory activity (93). An effect of gonadal steroids on gonadotropes is apparently modulated by intrapituitary opioids since estradiol and progesterone increase secretion of ß-endorphin (31). Interestingly, in addition to the observations implicating CRF in gonadotropin control, another hypothalamic releasing factor not usually associated with LH or FSH regulation, TRH, has been identified in gonadotropes (241) as well as its gene expression (242), although the role of the protein is still to be delineated. Furthermore, TRH release could be induced by GnRH (242). Somatostatin, too, has been observed in the anterior pituitary (243, 244), and somatostatin receptor mRNA has been detected in gonadotropes (245); somatostatin inhibited GnRH-stimulated LH release in vitro (246).

Other peptides for which some evidence exists for a role in regulating LH and FSH are CNP, NGF, neurotensin, and VIP.

CNP has been identified by immunohistochemistry in a subpopulation of gonadotropes in rat pituitaries. It is synthesized in the pituitary and is located primarily in the gonadotropes (247). CNP has been found to increase cGMP production in rat pituitary cells and in T3–1 cells by activating the B-type natriuretic peptide receptor, being markedly more potent than atrial natriuretic peptide or brain type natriuretic peptide in this regard (248). Northern blotting has revealed the presence of GC-B receptor transcripts in gonadotropes. CNP was not found to alter GnRH-stimulated LH secretion, but in contrast GnRH reduced CNP-stimulated cGMP accumulation in T3–1 cells (248). It has been suggested that CNP exploits a physiological autocrine mechanism to modulate LH release (247).

Recently neurotensin was observed to raise [Ca⁺⁺]_i in isolated gonadotropes and increase LH release from rat cells (51), possibly by cross-reacting with GnRH receptors (54). Neurotensin receptors have been identified in the anterior pituitary gland and indicate a target, probably including lactotropes, which responds by increasing Ca⁺⁺ influx (38). Neurotensin has been detected in the anterior pituitary gland of several species, including man (227, 249, 250), and persists after stalk section of the rat, suggesting there is local synthesis (250). Indeed, mRNA for neurotensin has been detected in the anterior pituitary and is responsive to estrogen levels (227), although whether this is related to gonadotropin control is debatable (251). Neurotensin antiserum (intravenous) had no effect on LH or FSH in either ovariectomized or ovariectomized-estrogen, progesterone-primed rats (252).

VIP added to T3–1 cells stimulated Ca⁺⁺ influx and only at high concentrations stimulated cAMP accumulation and PI turnover (106). However, in spite of those results on gonadotrope-derived cell line, there is meagre evidence for a role by VIP in LH regulation from other in vitro studies (75). Although ultrastructural studies detected VIP in the anterior pituitary gland only in lactotropes (253), VIP has been detected by immunocytochemistry in the pituitary of both male and female rats (254) and has been observed in cells other than lactotropes, indicating that the role of VIP in the pituitary is still to be fully defined. Other investigations observed that VIP and VIP mRNA in the pituitary of male and female rats altered in a manner that suggested a regulatory role for estrogen in expression of the VIP gene (255, 256). VIP mRNA was detected in the pituitary of humans (228). VIP did not affect LH in male rats when administered intratrially (257). VIP did not affect basal LH or FSH concentrations in human males; however, VIP augmented the LH response to GnRH, but not the FSH response (258). This is notable in that activity of VIP on gonadotropins in animal models has not been well established.

Also, high-affinity NGF receptors have been detected on gonadotropes (259), pointing to a role on the reproductive axis. NGF has been detected at gonadotropes, either as a product of local synthesis or bound to target cell receptors (259). In addition, secretion of NGF from anterior pituitary cells has been reported (260), suggesting that NGF has possible autocrine or paracrine activity. Furthermore, insulin-like growth factor I administration to GH-deficient male Ames dwarf mice was found to reduce the LH response to GnRH (261).

Additionally, the persistent presence of the key peptide, GnRH, occurred in anterior pituitary cell cultures (241), and expression of GnRH mRNA also occurs in the pituitary of rats (262) and humans (166). Thus GnRH of a local origin might also contribute to gonadotropin regulation.

	IX. Activity of Peptides in Vivo

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
Data complementary to that obtained in vitro are acquired by investigations of effects in vivo. In animal models the effect of peptide administration has been various, partly perhaps because of the modulatory capacity of the endocrine environment to alter peptide potency as discussed above. Converse experiments in which endogenous peptide activity is removed by administering antagonists or antibodies have also been carried out. It is often assumed that antibodies administered peripherally will act at the pituitary, although an influence at areas outside the blood-brain barrier, such as the median eminence, cannot be discounted. It has been suggested that some low molecular weight peptide antagonists are able to cross the blood-brain barrier and affect gonadotropin secretion by mechanisms acting in the hypothalamus, such as modification of GnRH secretion.

Endothelin-3 delivered intravenously to rats at proestrus, which had been given pentobarbital to block naturally occurring ovulation, stimulated secretion of LH and also FSH. The results suggested an activity of endothelin-3 at the pituitary (263). After infusion of endothelin-1 to human males, LH and FSH concentrations were unchanged, but endothelin-1 infusion enhanced GnRH-stimulated gonadotropin release (264).

Administration of galanin antibody induced a partial alteration of LH; the antibody blunted the LH preovulatory surge by reducing total output rather than lowering maximum peripheral concentration. In addition, FSH early secretion was reduced (265). Galanin, by contrast, has not been observed to stimulate basal or GnRH-stimulated LH or FSH concentrations in human females (266) or in males (267).

NPY administration in vivo enhanced GnRH-stimulated LH release (268), but only under certain endocrine (estrogen- and progesterone-modulated) conditions (214), and NPY acts in vivo via a Y-1 receptor subtype in the anterior pituitary gland (269). NPY immunoneutralization of male mice caused an increase in LH and in FSH and increased LH in castrated mice (270). Similarly, NPY antiserum (intravenous) increased LH in ovariectomized rats although, in this study, a site of action at the anterior pituitary gland was not favored (271). In contrast, during a steroid-induced LH surge anti-NPY antiserum inhibited the LH rise (25) as did a Y-1 receptor antagonist administered to proestrous rats or to pentobarbital-treated rats given GnRH (269). The suppression of the proestrous LH surge by inhibitors is not complete and indicates that, in the absence of NPY, suboptimal surges occur. The opposite effects (inhibition vs. increase) elicited by anti-NPY antisera in different studies presumably reflect the prevailing endocrinology and is another example of the care with which results must be assessed. NPY administration (intravenous) to men did not affect basal LH or FSH. However, in conjunction with GnRH, a potentiation of LH secretion occurred, and a lesser effect was observed with regard to FSH (272).

The administration of an oxytocin antagonist suppressed the LH surge in proestrous rats, suggesting that oxytocin has a crucial physiological role in LH production (215, 273). Conversely, injection of oxytocin advanced the LH and FSH surges in female rats (215). In addition, oxytocin enhanced GnRH-stimulated LH secretion in vivo in rats (173). Oxytocin increased LH release also in horses in vivo (28). The data concerning oxytocin illustrate the advantage of attending to the known characteristics of the peptide derived from animal models when designing human studies. An effect of oxytocin on baseline LH in women did not occur in some studies (274, 275, 276), but an advance of the LH surge after administration of oxytocin in a physiologically estrogenic environment, perhaps in concert with rising endogenous GnRH, has been observed (216). An effect of oxytocin was therefore observed when the properties of the particular peptide were incorporated into the protocol. A cyclic variation of peripheral oxytocin is widely reported (277, 278, 279), suggesting that oxytocin secretion is responsive to the environment and by implication oxytocin has an activity associated with the changing profiles of the reproductive hormones.

Intratrial administration of PACAP induced increased LH concentrations in male rats, apparently via an anterior pituitary gland site (257). PACAP did not affect basal or GnRH-stimulated LH or FSH in human males (258).

Administration of substance P antiserum (intravenous) had no effect on LH or FSH levels of ovariectomized rats, although injection of substance P (intravenous) to ovariectomized rats with estrogen priming stimulated LH (but not FSH) secretion. However, because substance P did not affect anterior pituitary gland cells from estrogen-primed ovariectomized rats in vitro in these studies, the investigators concluded the substance P effect was at the hypothalamus (89). On the other hand, other in vitro studies have detected effects of substance P at the pituitary (see above, Sections III and V). Substance P (subcutaneous) decreased the preovulatory surge of LH (90, 182) and reduced progesterone enhancement of GnRH-stimulated LH release. In the primate, substance P seems to be involved at the pituitary level in the regulation of the LH surge. Levels of substance P in the anterior pituitary were least when the estrogen-induced LH surge developed in ovariectomized monkeys (239). Substance P infusion to human males caused an increase in a dose-dependent fashion in LH levels; however, FSH was unaffected (280). On the other hand, specific antagonist of the NK1 receptor (RP67580) significantly increased the LH surge in rats (182). While substance P inhibited the FSH surge, RP67580 had no effect on the FSH surge.

EGF administration (intravenous) affected the release of LH and FSH in cycling Merino ewes in a manner that was dependent on the stage of the cycle (281, 282). Although the action by EGF on the gonadotropins was possibly indirect via the ovary, more recent results allow an interpretation that includes a pituitary component to its activity (111).

In vivo results, therefore, supplement observations obtained during in vitro studies. When an effect is observed in vivo, it engenders more confidence that the peptide possesses underlying physiological activity. It seems, therefore, that the mechanisms by which gonadotropins are regulated include the various effects of a number of peptides, acting directly at the pituitary.

	X. Interaction Among non-GnRH Peptides

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
Extending the reasoning that peptides can augment or inhibit the activity of the key peptide, GnRH (Section V), non-GnRH peptides might interact among themselves at the pituitary, an aspect that has received almost no attention. This is perhaps surprising. The timing of delivery of peptides from the hypothalamus to the pituitary via the portal blood system would perhaps provide some indication whether peptides that would likely interact are present at concurrent or sequential times. However, the presence of intrapituitary peptides (Section VIII) could complicate interpretations.

A possibility for interactive regulation is suggested by the recent observation that the augmentory effect of oxytocin on GnRH-stimulated LH release is suppressed by cAMP (175). It is known that NPY is a peptidic inhibitor of cAMP formation (283, 284). Hence, it is plausible that NPY-mediated reduction of cAMP is a physiological component of oxytocin-enhanced GnRH-stimulated LH release.

A peptidic coordination of a different type is suggested by the observation that endothelin stimulates substance P secretion (285). Thus, it is reasonable to speculate that endothelin-enhanced secretion of LH is followed by substance P-mediated reduction of LH levels at the decline of the LH surge, after substance P release has been increased by prior endothelin activity.

In bovine corpora lutea, oxytocin stimulates endothelin-1 from luteal microvessel endothelial cells (286). Speculating across tissues, this suggests that a rise of endothelin in the pituitary induced by factors of proestrus could be augmented in the presence of oxytocin.

Because GnRH receptors can be unmasked by certain factors, it seems plausible to propose that unmasking of receptors of peptides other than GnRH can also occur perhaps under the influence of complementary peptides. The implication is that for the full expression of the effects of one peptide to occur, another must also be present at the gonadotrope concurrently or at a prior time.

Within the cell there is potential for the sequential modulation of distinct enzymes/isoenzymes to be linked to separate processes that mediate the diverse activities of gonadotropes (141). Thus, to produce a fully coordinated functioning of the gonadotrope cell, and therefore of the reproductive endocrine cascade, the appropriate timely stimulation of the signal-mediating enzymes must occur. It is feasible that different peptides will selectively stimulate different isoenzymes of a transduction pathway.

There are a number of peptides that act on the pituitary. That physiological metabolism is efficient is often invoked as a useful working assumption. In a waste-free biology all peptides observed to have activity in the experimental situations which approximate physiological conditions will have an endogenous in vivo role. In that case, all these peptides considered here must be included in a physiological network. The peptides must interact, among themselves and with GnRH, and be coordinated by processes that can be modulated according to endocrine status (Fig. 4). It is a field of study with potential theoretical and clinical profit.

View larger version (21K): [in this window] [in a new window]   Figure 4. Some established, hypothetical, and speculative processes involving peptides in the regulation of the LH surge at the level of the anterior pituitary gland. A filled circle represents action of peptide directly on gonadotrope; an arrowhead represents interactions between peptides. Numbers in square brackets correspond to the interaction referred to in the diagram. [1–8], peptides can augment GnRH. [9,15–17,19–21,23,26], peptides can stimulate LH independently. [14,18,22], peptides can interact with another non-GnRH peptide. [10–12], peptides can inhibit GnRH activity. [13,24,25], peptides exert negative modulation of LH release. In the production of the rising phase of the LH surge, LH release is stimulated by [9] GnRH, [15] endothelin (ET) (47 ). Additionally, ET selectively stimulates LH or FSH release using different G proteins (52 ). LH release is stimulated by [16] galanin (GAL) (10 ), [17] NPY (61 62 63 ), [19] oxytocin (OT) (68 69 ), [20] PACAP (74 75 ). Additionally, PACAP differentially modulates expression of gonadotropin subunit genes (74 ). LH release is stimulated by [21] substance P (SP) (90 91 ), [23] opioids (31 ), [26] EGF (96 ). Additionally, EGF stimulates synthesis of mRNAs. [14] OT stimulates ET production (286 ). GnRH-stimulated LH release is augmented by [1] ET (50 ), [2] GAL (10 ). Additionally, GAL augments binding of GnRH to GnRH receptors (56 ). GnRH-stimulated LH release is augmented by [3] NPY (168 ). Additionally, NPY augments binding of GnRH to GnRH receptors (56 ), and NPY unmasks GnRH receptors (171 ). GnRH-stimulated LH release is augmented by [4] OT (174 ). [18] NPY suppresses cAMP production and so enhances OT augmentation of GnRH-stimulated LH release (283 284 ). GnRH-stimulated LH release is augmented by [5] PACAP (75 ). Additionally, PACAP imposes a pulsatile pattern on PACAP stimulation (78 ). [6] EGF unmasks GnRH receptors (117 ). [8] GnRH self-primes its own activity. [7] OT augments GnRH self-primed response (174 ). During the declining phase of the LH surge [10] ET reduces the response to GnRH (50 ), [11] SP has an inhibitory action (182 ) and [22] ET stimulates SP release (285 ). [12] Opioids inhibit GnRH-stimulated LH release (95 ) and decrease the number of GnRH receptors (118 ). Additionally, [24] opioids inhibit basal LH release (31 ). Tonic regulation/modulation of LH release is exerted by [13] inhibitory activity of NPY (66 ) and [25] opioids (31 ).

GnRH itself, unquestionably, is a key regulating peptide that has multifarious effects, including priming, desensitization, synthesis, and secretion. These effects are apparently controlled by both dose and pulse rate (amplitude and frequency). Different second messengers are used for different purposes, e.g., acute secretion and priming. The distinct effects of this well studied peptide illustrate the possibilities that peptides can display. The diverse effects point to the problem in defining the roles of other peptides, and GnRH probably elicits still-to-be-defined autocrine/paracrine products that affect how the GnRH itself acts on LH.

Does each of the other peptides have all effects displayed by GnRH; do they have a specialized and restricted activity; do they perform several functions but not with equal efficacy; do they mediate most of the numerous functions of the gonadotrope; or are they backup peptides only to be used when the primary hormones fail?

	XI. Processes Other Than Secretion That Are Modulated by Peptides

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
It is possible that all or some of the peptides have more than one type of role. The peptides can be delivered from the hypothalamus, which is the traditionally postulated source, or perhaps from within the pituitary (see Section VIII). Secretion of LH and/or FSH is the parameter that has most often been used to identify possible peptidic contributors to the endocrinological network that regulates gonadotropin activities. However, other effects have been noted, too. LH synthesis has been induced by oxytocin (296), and an increase in the extent of GnRH receptor binding has been produced by NPY (56). For oxytocin, investigations performed in a series of studies have led to a suggestion that oxytocin might sensitize the pituitary before stimulation by GnRH (174). A similar proposal, based on the presence of peptide in portal blood, has been proposed for NPY (25). It has already been proposed that the major activity of PACAP might be in processes other than secretion (74, 81). Additionally, it has been suggested that PACAP may be a regulator of gene transcription rather than a releasing factor or, in some circumstances, an auxiliary releasing factor of pituitary hormones (297). Furthermore, the mode of PACAP secretion in vivo may be a determinant of the differential expression of the gonadotropin subunit genes, possibly by regulated stimulation of the cAMP/PKA and PKC pathways, both of which are activated by PACAP (298). During the LH surge EGF might stimulate synthesis of new gonadotropin subunit mRNAs (111). Thus, one should be cautious of suggesting minor roles to these peptides on the basis that the potency with which they induce increased gonadotropin secretion is less than that of GnRH. The relevance of such speculation to physiological control of gonadotropins is unclear. In this regard it can be noted that endothelin does elicit LH release with high efficiency, but has a more rapid desensitization profile (50), providing an illustration of a non-GnRH peptide potentially having a particular role, namely a rapidly initiated but not sustained stimulation of gonadotropin. The roles of the peptides can be considered in the light of evidence suggesting that different intracellular processes mediate distinct effects. Genes that are related to gonadotropin subunits are differentially regulated by GnRH by selective use of either the Ca⁺⁺-dependent pathways, which play a greater role in stimulation of -subunit gene expression, or the PKC-dependent pathways, which are of more importance in stimulating ß-subunit gene transcription (299). Thus by potentiating particular processes a peptide would be able to modulate GnRH-mediated effects.

In various places in this review (including this section), mention has been made of the variety of effects of peptides. These include effects on gonadotropin mRNA, stimulation of synthesis of gonadotropin, unmasking of receptors, stimulation of secretion of possible paracrine factors, increase of GnRH binding to gonadotropes, augmentation or inhibition of GnRH-stimulated gonadotropin secretion, and increased sensitivity for GnRH-stimulated LH release. With these possibilities in mind, it is clear that in the cases where stimulated secretion of gonadotropin is not the primary or only function of a peptide, interpretation of results using that parameter becomes particularly awkward.

In addition to a direct action of peptides on gonadotropes, peptides might act by means of modulatory intermediate compounds so that paracrine effects are induced. For example, IL-6 stimulates LH and FSH release in vitro (300, 301), and IL-6 affects calcium mobilization in gonadotropes, possibly indirectly by means of a substance from another cell type (302). PACAP binds to folliculo-stellate cells (104), and PACAP has been identified as potentially able to stimulate IL-6 secretion (303) from folliculo-stellate cells, which are important in regulating anterior pituitary gland function (304) and which are suggested to modify the process of GnRH self-priming. The observations indicate the potential importance of having a diverse array of cell types for complete regulation of gonadotropin levels. Therefore, in these sorts of cases, conditions that enable expression of both folliculo-stellate cell function and gonadotrope function are necessary for the peptide to exhibit full gonadotropin- associated activity.

Other peptides and nonpeptide factors are also potentially part of the network. These include, in addition to steroids and ions, the nucleotide, ATP (305, 306, 307), and possibly the gaseous transmitter, nitric oxide (NO) (308), originating from within the gonadotrope itself and having an autocrine mechanism (309). NO is also produced by folliculo-stellate cells (310, 311). NO synthase (NOS) activity is indeed increased in gonadotropes by GnRH, although NOS in folliculo-stellate cells is not similarly responsive (312). The place of these factors is unknown.

The peptides that affect LH have also been observed to affect other physiological systems regulated by the anterior pituitary gland, including those mediated by the classic anterior pituitary gland hormones. Hence, there might be integration with other systems. A few examples will illustrate the possibility. NPY and GnRH have been observed to affect not only LH, but also PRL, GH, and ACTH levels (313), indicating that there is smudging of responsive specificity that must ultimately be incorporated into a fully delineated scheme. PACAP stimulation of GH release was achieved by invoking a different mechanism to that which regulates LH, the former via a pathway utilizing cAMP and PKA, the latter via an IP₃-dependent mechanism (80, 82). Thus, there is the possibility of selective controls directed at particular intracellular processes. Further complexity is indicated by the distribution of LH-regulating peptides, e.g., substance P in TSH-containing cells (232), and of galanin in PRL-containing cells (226). Additionally, a physiological stimulus might affect the release of more than one anterior pituitary hormone, including an effect on LH possibly as an adaptive modulation, e.g., stress that demands reduction in LH and also an increase in ACTH. Thus, the processes impinging on peptide levels could be contradictory, causing variations that are difficult to interpret at this stage of our knowledge. It is becoming less and less acceptable to employ the traditional concept of an independently acting collection of cells in the anterior pituitary gland as an explanatory model. Thus an effect of a physiological event that modifies levels of a regulatory peptide to alter gonadotropins might alter other pituitary hormones that the peptide affects. Conversely, an effect to alter activity of a nongonadotrope pituitary cell that contains a gonadotrope-regulating peptide could consequentially alter gonadotrope function.

The roles of the peptides are hard to define. Examples of the quandaries that arise are provided by NPY and oxytocin. In spite of a substantial body of evidence pointing to involvement of the peptides in LH/FSH control, when the peptides are absent, in mice, fertility remains (314, 315). Knockout mice have also been generated for endothelin-1 (316), endothelin-3 (317), and ET-B receptor (318), but because the mice do not survive to adulthood, the reproductive function of mice in the absence of endothelin activity has not yet been discerned. Similarly, mice devoid of EGF receptor have been produced (319, 320), but they also do not survive to reproductive maturity.

	XII. Summary and Conclusion

Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 
There are several lines of evidence that point to peptides participating in the regulation of LH and/or FSH levels by action at the pituitary. This evidence includes altered secretion of gonadotropins from the anterior pituitary cells or tissue in vitro when exposed to the peptide. Additionally, modification of GnRH-stimulated LH/FSH secretion has been observed. Furthermore, there is potential for a separately modulated interaction with the primed response. Another potential of action is by interaction among non-GnRH peptides on gonadotropin-regulating processes, although there are no good data available on this aspect. Other observations, consistent with a pituitary role for the peptides in modulation of LH, include detection of the peptides in portal blood, detection of high-affinity receptors or receptor mRNA in the pituitary, and detection of intrapituitary peptide or peptide mRNA in the pituitary. The modulation by steroids of both concentrations and type of activities provides a further level of physiological refinement.

There is, however, some confusion regarding the involvement of these peptides in gonadotropin control. The reasons can be seen by considering aspects of investigations. There are experimental variations such as 1) species studied, e.g., NPY has been reported to have an effect on LH secretion from rat cells (168) but not on sheep anterior pituitary tissue (64), and substance P inhibits GnRH-stimulated release from rat cells (182) but potentiates the response in prepubertal porcine cells (92); 2) the steroidal conditions under which the study is performed, e.g., NPY has opposite effects in certain endocrine environments, augmenting GnRH-stimulated LH release in proestrus-like conditions (168), and inhibiting in metestrus-like environment (66); 3) the type of cell preparation, e.g., responsiveness to substance P might depend on whether cells in overnight culture were in separated or clustered state (91); 4) the time course considered, e.g., oxytocin that might induce marked LH release from pituitary cells after a longer length of incubation than GnRH requires (68); 5) length of exposure to peptide, e.g., endothelin that augmented or inhibited GnRH-stimulated LH release (50); 6) In addition, it is possible that the traditional endpoint selected in such studies, namely, observation of gonadotropin secretion, is not necessarily the most important for these peptides (56, 81, 117).

Unfortunately, at this stage a definitive answer to the question "What do the peptides actually do?" cannot be provided and we remain tantalized by the glimpses of potential roles. Perhaps in a few years an updated review will be able to include a more complete answer. It is necessary for the full understanding of LH control that not only the properties of the peptides in isolation be characterized but also their interactions.

	Footnotes

 
Address reprint requests to: John J. Evans, University Department of Obstetrics and Gynaecology, Christchurch Women’s Hospital, Private Bag 4711, Christchurch, New Zealand.

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Top Abstract I. Introduction II. Between the Hypothalamus... III. Direct Modulatory Action... IV. Pituitary Receptors V. Interaction of Peptides... VI. Self-Priming by GnRH... VII. Steroids and the... VIII. Intrapituitary Peptides IX. Activity of Peptides... X. Interaction Among non-GnRH... XI. Processes Other Than... XII. Summary and Conclusion References

 

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