Role of the hypophyseal neurointermediate lobe in the dynamic release of prolactin

BRIEF REVIEWS Role of the Hypophyseal Neurointermediate Lobe in the Dynamic Release of Prolactin

decrease precipitously and remain relatively stable. After the pups are returned and allowed to suckle, circulating PRL

L. Stephen Frawley

higher than baseline and is sustained for at least 1 h. Perhaps the most intriguing aspect of

The dynamic release of prolactin (PRL) occurs in a region of the anterior pituitary lobe (AP) that receives its blood supply primarily from the hypophyseal neurointermediate lobe (NIL) via the short portal vessels. This relationship, coupled with a growing body of supportive evidence, suggests that the hypophysiotropic signal mediating the massive discharge of AP PRL derives from the NIL rather than the hypothalamic median eminence, as previously believed. Moreover, a major component of this signal appears to be a-MSH. (Trends Endocrinol

1994;5: 107-l 12)

Metab

The neurointermediate rat hypophysis regulating

lobe (NIL) of the

plays an essential

the dynamic

role in

release

of pro-

lactin (PRL) from the anterior (AP) (cf. Ben Jonathan

pituitary

and Liu 1992).

This is evidenced by reports that surgical removal

of the NIL blocks

the

acute

release of PRL induced by two physiologically relevant trogen

stimuli:

treatment.

suckling

The

and es-

NIL communi-

stimulating hormone) secreted by the rat NIL. Thus, it appears that the NIL, through the mediation of this peptide, plays a requisite role in the dynamic release of PRL. This review summarizes evidence relevant to such a possibility. For the sake of clarity and simplicity, information about suckling- and estrogeninduced PRL release are considered separately.

cates with the AP via the short portal vessels, and chemical vert the effects changes

signals

of evocative

in PRL cell function

that constimuli

to

are proba-

bly delivered by this route. Recent experiments indicate that the NIL contributes two relevant activities to these processes. The first of these appears to be released by the suckling mammotropes

stimulus

and renders

more responsive

to PRL-

releasing agents. The other is induced by estrogen

and acutely recruits

PRL-releasing population. sponsiveness

cells

Interestingly,

variant

of

additional

the secretory both

and recruitment

can be mimicked ated

into

the reactivities

in vitro by the diacetyla-MSH

(melanocyte-

L. Stephen Frawiey is at the Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA.

TEM Vol. 5,No.3,1994

??

Suckling-Induced Prolactin Release

Prolactin Response to Nursing: The Responsiveness Phenomenon In freely behaving lactating rats allowed continuous access to their litters, circulating PRL levels tend to be high and randomly episodic, and the pattern of secretion is susceptible to modification by the suckling stimulus per se, auditory cues, circadian rhythms, and probably other variables yet to be identified (Nagy et al. 1986, Terkel et al. 1972, Sodersten and Eneroth 1984, Mattheij et al. 1985). Because this pattern of PRL release is too chaotic for experimental purposes, most investigators who study this phenomenon utilize the following system developed by Grosvenor et al. (1979). When lactating rats are separated from their pups for 4 h or more, serum PRL levels

01994,

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concentrations remain low for 5 min, increase by 10 mitt, and reach a maximum by 30 min that is 50 to 100 times

this phenomenon is the dramatic change in mammotrope responsiveness that occurs subsequent to the initial application of the suckling stimulus. In this regard, a high dose of TRH is reported to cause only a small transient elevation of plasma PRL when injected into lactating rats separated from their pups for several hours. However, the PRL secretory response to TRH injection is amplified many times when mothers are first suckled by their pups for just 10 min, a stimulus which by itself evokes only a modest increase in serum PRL (Grosvenor and Mena 1980). Moreover, the sensitivity of mammotropes is also enhanced under these conditions, since a lOOOtimes lower dose of TRH given after a brief nursing episode increases serum PRL to levels usually attained after a normal bout of suckling. Similar results are obtained when vasoactive intestinal peptide (VIP) or morphine is substituted for TRH in this experimental model (Neil1 et al. 1982, Callahan et al. 1988). Thus, suckling appears to prepare the AP to respond to agents that release PRL by a direct pituitary action.

Current Model for Hypothalamic Regulation: Strengths and Weaknesses The events that regulate the massive discharge of PRL after suckling comprise an elegant and intricate neuroendocrine reflex arc with a neural afferent limb (from the nipples to the hypothalamohypophyseal complex via the spinal cord and midbrain) and a humoral (hormonal) efferent component. This system has served as the focus of intense investigation for the better part of the past two decades because it lends itself well to experimental manipulation. Although much progress has been made in identifying neuronal systems involved in this process, the precise nature of the

107

terminal

signal

for

PRL

release

still

remains elusive. A consensus developed over the last dozen years holds that the hypophysiotropic signal mediating the sucklinginduced release of PRL travels from the median eminence to the adenohypophysis via the long portal vessels of the hypothalamohypophyseal portal system. This message is believed

to take the form of a

transient reduction in the secretion of hypothalamic dopamine coupled with an increase in the release of one or more PRL-releasing factors such as TRH or VIP. Consistent with this view are reports that (a) passive immunization to VIP (Abe et al. 1985), or pretreatment with a dopamine agonist (Grosvenor et al. 1980), severely attenuates suckling-induced PRL release; (b) simulation of a nursing episode by electrical stimulation of a mammary nerve trunk transiently decreases the concentration of dopamine in hypophyseal portal blood (de Greef et al. 198 1, de Greef and Visser 1981, Plotsky and Neil1 1982a) and increases that of TRH (de Greef and Visser 1982); (c) suckling causes a very brief reduction of median eminence dopamine, as measured by push-pull perfusion in conscious rats (Rondeel et al. 1988); and (d) transient removal of dopamine from pituitaries perifused in vitro modestly potentiates the stimulation of PRL release by TRH (Fagin and Neil1 1981, Martinez de la Escalera et al. 1988). Despite the existence of supportive evidence, certain aspects of the current model are difficult to reconcile with more recent experimental findings. For instance, some investigators have been unable to confirm the occurrence of dynamic changes in the secretion of TRH in response to nursing (Rondeel et al. 1988), thereby raising questions about the premises upon which this model is built. In addition, attempts to recreate even semiquantitatively the in vivo re-

model is that it does not integrate

two

changes

in mammotrope

responsiveness that favor PRL release are early and fundamental events for the suckling-induced release of the

completely abolishes the induced rise in PRL (Murai Jonathan 1987). It appears, that a PRL-modulating signal from the NIL to the AP via

hormone (Grosvenor and Mena 1980, Neil1 et al. 1982, Callahan et al. 1988).

sucklingand Bentherefore, delivered the short

The NIL is an essential component of the PRL-releasing signal activated by nursing; removal of the NIL com-

portal vessels must be integrated with those that traverse the long portal vessels

pletely abolishes the response (Murai and Ben-Jonathan 1987).

from the median eminence to the adenohypophysis. While the biochemical

The NIL communicates with the adenohypophysis via blood passing

nature of the NIL contribution remains to be elucidated, there is evidence to indicate that it could be attributable, at least in part, to a PRL-releasing factor different from those identified to date (Murai and Ben-Jonathan 1987, Hyde and Ben-Jonathan 1988, Laudon et al. 1990). A final concern with the current model is that its treatment of dopamine’s effects requires updating and reevaluation; it focuses entirely on the inhibitory and overlooks the stimulatory actions of the catecholamine on PRL release. Thus, it does not account for the elegant studies by Denef et al. (1980), which have been confirmed and extended by other laboratories (Kramer and Hopkins 1982, Burris et al. 1991), that show dopamine concentrations 1000 times lower than those required for inhibition can actually stimulate PRL release. In fact, Burris et al. (1991) utilized an in vitro perifusion system to demonstrate that such low doses of dopamine are even more effective than complete withdrawal of the agent in evoking a massive discharge

of PRL.

Expanded Model: The Case for a Mammotrope Responsiveness Activity of Neurointermediate Lobe Origin The aforementioned concerns regarding the current model invite speculation about the existence and participation in this process of a mammotrope-respon-

sponsiveness changes by varying dopamine and TRH patterns in vitro have met with limited success (Fagin and Neil1 1981, Martinez de la Escalera et al. 1988). Thus, modest reciprocal changes in portal blood concentrations of TRH and dopamine are far from sufficient to

siveness agent. It is proposed that the nursing stimulus induces the release of such an activity from the NIL into the blood and that is delivered to the AP via the short portal vessels. It is further hypothesized that this agent brings about the striking augmentation of mam-

account for the striking augmentation of responsiveness and consequent massive discharge of PRL that occur after suckling (Plotsky and Neil1 1982b). An additional disturbing aspect of the current

motrope responsiveness that is characteristically evoked by nursing. The case for the existence of such an activity of NIL origin is summarized in outline form as follows:

108

Dramatic

experimental observations that seem to be exceedingly relevant. The first of these is that removal of the NIL from lactators

01994,

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through the short portal vessels (Adams et al. 1965/1966, Porter et al. 1967). NIL-conditioned blood perfuses primarily the inner zone of the AP; this is evidenced by reports that the inner region exhibits the lowest degree of necrosis after destruction of the long portal vessels (Adams et al. 19651 1966, Porter et al. 1967). Responsiveness changes that occur after a brief suckling stimulus are manifested almost exclusively by mammotropes within the inner zone of the AP (Nagy et al. 1991). The expanded model for regulation of suckling-induced PRL release offers several improvements over the currently adopted version. First, the controversy as to whether dynamic changes occur in stalk-blood concentrations of TRH and dopamine is diminished somewhat in importance. With the expanded model, regulation would be effected, at least in part, by modulation of target cell (mammotrope) responsiveness, rather than by just varying the amount of hypophysiotropic signal delivered via stalk blood. It is important to note that this model is not necessarily at variance with the consensus view that a diminution of dopamine “tone” is required for the nursing stimulus to induce PRL release in vivo. This concept is based on the observation that injection of a dopamine agonist blocks the PRL response to suckling (Grosvenor et al. 1980). Generally, this finding has been interpreted to mean that a reduction in stalk-blood dopamine

(secreted by the tudopaminergic system) is a final step in suckling activation of PRL release. An equally plausible explanation, however, is that administration of dopamine agonist masks a sucklinginduced diminution in activity of the

beroinfundibular

TEM Vol.5,No. 3,I994

several observations, the most salient of which are summarized as follows. First,

be critically

a-MSH is a major secretory product of the NIL, and its secretion is tonically

that surgical removal of the NIL (LOBEX)

siveness agent would be under the inhib-

completely

blocks the peak phase of the

itory control

inhibited

proestrous

PRL surge and consequently

tuberohypophyseal

dopaminergic

(THDA) that terminates this scenario,

system

in the NIL. In

the secretion

of a respon-

of the THDA system,

and

thus a reduction in dopamine “tone” caused by nursing would lead to a disinhibition of release of this agent from the NIL. It is significant that a leading candidate to subserve a role as a responsiveness regulator is a-MSH (see below), whose secretion is tonically inhibited by dopamine derived from the THDA system (Lindley et al. 1988). Another distinct advantage of the expanded model is that it provides an explanation for the obligatory participation of the NIL in the suckling-induced release of PRL. The secretion of a responsiveness agent by the NIL is not mutually exclusive of the possibility (raised by Ben-Jonathan and coworkers) that the NIL may also produce a prolactinreleasing factor (PRF). As indicated earlier, the participation of a releasing factor in this phenomenon is likely, and the issue of whether it is delivered to the adenohypophysis via the short or long portal vessels does not compromise the validity of this hypothesis. A final positive aspect of the expanded model is that it takes into account the stimulatory as well as the inhibitory actions of dopamine on PRL release. A brief suckling interval renders pituitary cells responsive to the PRL-releasing actions of low-dose dopamine (Hill et al. 199 1). Interestingly, mammotropes from nonsuckled rats can be made responsive to the stimulatory effects of dopamine by concurrent exposure in vitro to a-MSH, a NIL hormone that appears to be released in response to suckling (Hill et al. 1991). In summary, the current model for hypothalamic regulation of sucklinginduced PRL release requires updating

by dopamine

(Taleisnik

1978,

important.

cally, Ben-Jonathan’s

More

specifi-

group has shown

Eipper and Mains 1980, Akil et al. 1984); thus a requisite reduction in dopamine tone would lead to its release. Second, NIL stores of a-MSH are rapidly depleted within minutes of suckling (Taleisnik and Orias 1966, Deis and Orias

severely attenuates the total amount of the hormone released during the entire process (Murai et al. 1989). To explain this observation, the same group invoked the participation of a NIL-derived PRF. As discussed earlier, such an activity

1966), suggesting a cause-and-effect relationship between a-MSH and the dynamic release of PRL. Third, in vivo immunoneutralization of a-MSH severely attenuates the PRL response to suckling, demonstrating that the NIL peptide is required for full manifestation of the response (Hill et al. 1994). Finally, aMSH can mimic, in vitro, the effects of nursing by imparting responsiveness to at least one PRL-releasing agent-lowdose dopamine (Hill et al. 1991). When considered as a whole, these observations comprise a strong argument that a-MSH functions in the proposed capacity of mammotrope-responsiveness agent.

does indeed appear to be present in extracts of NIL tissue, but its precise role in this phenomenon has yet to be defined (Ben-Jonathan and Liu 1992).

??

Estrogen-Induced Release

Characteristics to Estrogen

Prolactin

of the Prolactin Response

A second major physiologic stimulus for the acute release of PRL in mammals is estrogen (E). A facilitative regulatory role for E is most evident during the 24 h preceding the morning of proestrus,

Studies aimed at elucidating the neuroendocrine events mediating the E,induced PRL surge in intact animals have been complicated by temporal constraints: in the 24 h required for E, to induce a “natural” surge involving a central action, the steroid can also act directly on the adenohypophysis to increase PRL synthesis and storage as well as the mitotic activity of mammotropes. This problem has inspired attempts to develop models in which induction of the surge is telescoped into a more narrow time frame. The most recent and successful of these models was developed by Murai and Ben-Jonathan (1990) and involves intravenous injection of moderate amounts of E, into conscious rats ovariectomized (OVX) l-2 weeks earlier. Under these conditions, E, induces a five- to sixfold increase in circulating PRL, which reaches a peak between 2.5 and 3.0 h after treatment and returns to preinjection levels by 4 h. Interestingly, this acute PRL response to E, is severely attenuated in OVX rats subjected to LOBEX several days earlier. The profound attenuation of the E,-

mary has been to provide such reorientation by developing an expanded working model which invokes the participation of a mammotrope responsiveness activity

when a rising blood E titer triggers a surge of PRL as well as LH (Neil1 1980, Arbogast and Ben-Jonathan 1988, Murai et al. 1989). The estrogen dependency of this phenomenon was elegantly demonstrated two decades ago by Neil1 et al. (1971), who abolished the proestrous PRL surge by administration of estradiol (E,) antiserum and reversed this inhibition by concurrent injection of diethylstilbestrol, a synthetic E. Until recently, it was generally believed that E, exerted the aforementioned effects by acting at the adenohypophysis, where it

and is entirely consistent with recent experimental findings.

worked directly on mammotropes to augment PRL gene expression (Lieber-

evoked surge is considered reasonably specific for PRL (in this and the above model) since the patterns of LH release in sham-operated and LOBEX groups were virtually identical. Yet, despite the availability of an appropriate in vivo model, little progress has been made toward understanding the mechanism by which the NIL mediates E, induction of PRL release. Such an understanding was facilitated by the recent development of an in vitro model system that

man et al. 1982) and to antagonize dopamine inhibition of PRL release (Raymond et al. 1978). There is strong evidence, however, to indicate that neuronal input involving the NIL may also

enables partitioning of the effects of E, and NIL secretory products on various parameters of mammotrope function. The system uses OVX rats as the tissue source, and the time course for E, action

and expanding in order to become better aligned with the profusion of new and relevant evidence. The goal of this sum-

more

Is a-MSH the Mammotrope

Responsiveness

Agent?

The view that a-MSH subserves the role of responsiveness agent is based on

TEM Vol.5,No. 3,1994

91994,

Elsevier Science Inc., 1043.2760/94/$7.00

109

SUCKLING

ESTROGEN

cells

from

a quiescent

to

an

active

secretory state. It therefore seems reasonable to propose that the secretion of such an activity from the NIL provides an explanation as to how this lobe plays a requisite role in Ez-induced PRL release.

Is ct-MSH the Mammotrope Recruitment Agent?

MELANOTROPE

The following is a succinct summary of several findings relevant to this possibility. The most important among these are

aMSH Imp&

RESPONSIVENESS of preexisting PRL secretors to the stimulatory effects of dopamine

aMSH Indices

R5t!~:$F~T

cells into the secretory pool

Figure 1. Dual roles of a-MSH in the dynamic release of prolactin (PFU).

(3 h) is identical to that obtained with the OVX rat in vivo. Using this model system, Ellerkmann et al. (1991) determined that E, acutely stimulates NIL cells to secrete an activity that increases PRL release in two ways: (a) by augmenting the secretory capacity of individual mammotropes and (b) by rapidly recruiting additional PRL cells into the secretory population. The first of these effects is probably the consequence, at least in part, of the NIL-derived PRF proposed by Ben-Jonathan and colleagues. The recruitment activity, however, appears to be quite novel and has served as a primary focus for research in this area.

The Case for a Mammotrope Recruitment Activity The initial arguments for the existence of mammotrope recruitment and responsiveness agents are very similar in that the NIL is believed to be an essential component of the response, that this organ is provoked by an appropriate stimulus to secrete an activity that is delivered to the AP via blood passing through the short portal vessels, and that the response is manifested almost exclusively by the AP region (inner zone) perfused by this blood (Porter and Frawley 1992). Additional considerations

110

specific to the case for a mammotrope recruitment agent are summarized here as follows: 1. Concurrent exposure of AP cells to E, and NIL ceils rapidly increases (by -12%) the proportion of PRL-secreting cells (Ellerkmann et al. 1991). This response occurs far too quickly (3 h) to be attributed to mitosis of preexisting PRL secretors, and immunocytochemical analysis revealed that the recruited population does not correspond to cells that were previously able to synthesize and store, but not release, the hormone (Porter et al. 1992). Virtually all of the additional PRL secretors recruited by combined E,NIL cell exposure are mammosomatotropes-cells that release both GH and PRL (Porter et al. 1992). The rapid induction of PRL secretion in the recruited cells appears to require translation but not transcription of the PRL message, suggesting that posttranscriptional mechanisms regulate the emergence of PRL secretors (Porter et al. 1992). To summarize, these results suggest that E, stimulates NIL cells to release a mammotrope recruitment activity, which converts presumptive PRL

0 1994, Elsevier Science Inc., 1043-2760/94/$7.00

the observations that the E,-dependent, proestrous PRL surge in rats is accompanied by an increase of circulating a-MSH (Khorram et al. 1985), and that pituitary a-MSH in rats is depleted within 6 h after injection of E, (Taleisnik and Tomatis 1969). Additional evidence favoring aMSH as a recruitment agent is that in vitro immunoneutralization with an antiserum directed against the peptide abolished the recruitment of PRL secretors induced by E, stimulation of NIL cells (Ellerkmann et al. 1992). Moreover, a-MSH alone could completely substitute for combined NIL-E, treatment by evoking the recruitment response in vitro (Ellerkmann et al. 1992). Taken together, the available evidence points to a-MSH as the NIL agent that mediates Ez-induced PRL release by recruiting additional mammotropes.

??

Overview

Results derived from two interrelated models provide compelling evidence that the hypophyseal NIL subserves a regulatory role in the dynamic release of PRL, and that it does so through the mediation of two relevant activities (Figure 1). One of these is induced by suckling and rapidly renders mammotropes more responsive to the actions of PRL-releasing stimuli, whereas the other is induced by E, treatment and acutely recruits additional mammotropes into the secretory pool. The common thread that ties both of these models together is that the active principle appears to be a-MSH. Despite the wealth of evidence favoring the involvement of a-MSH in the dynamic regulation of PRL secretion, the mechanisms by which it exerts its effects on mammotropes remain obscure and raise a number of provocative questions. For example, what are the types and functional characteristics of receptors gov-

TEM Vol.5,No. 3,1994

erning

responsiveness

changes?

More

specifically, are any of the recently identified melanocortin receptors (Mountjoy et al. 1992) present on mammotropes,

or

could a-MSH act by binding to and inhibiting the activity of the dopamine D, receptors, as has recently been demonstrated by Florijn et al. (1991 and 1992)? What postreceptor events underlie the development of responsiveness changes? The involvement of cytoskeleta1 elements in this phenomenon is strongly suggested by the dominant role that a-MSH plays in chromatophore movement in lower vertebrates (Moellman et al. 1973) coupled with reports that a transient suckling stimulus rapidly causes centrifugal migration of secretory granules in mammotropes (Chang and Nikitovitch-Winer 1976) as well as a shift in tubulin dynamics to favor microtubule formation (Ravindra and Grosvenor 1988 and 1990). Conceptually similar questions about receptor activation and transduction also pertain to the recruitment of mammotropes by E,. In addition, an intriguing and unique aspect of this latter phenomenon relates to the issue of how a-MSH overrides the posttranscriptional block to PRL synthesis. As tantalizing as each of these questions may be in isolation, their resolution is clearly complicated by the fact that the responsiveness and recruitment phenomena are manifested only at the whole animal level. Thus, a multifaceted approach involving studies at several levels of organizational complexitycellular, molecular, and organismalwill be required to gain a comprehensive understanding about the neuroendocrine mechanisms governing the dynamic release of PRL.

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