Regulation of prolactin secretion at the level of the lactotroph.

PHYSIOLOGICAL REVIEWS Vol. 70, No. 2, April 1990 Printed in U.S.A.

Regulation of Prolactin Secretion at the Level of the Lactotroph S. W. J. LAMBERTS

AND R. M. MACLEOD

Department of Medicine, Erasmus University, Rotterdam, The Netherlands; and Department of Medicine, University of Virginia, Charlottesville, Virginia

I. Introduction . .... .... ..... .... .... ..... .... .... ..... .... .... ..... .... .... ..... .... .... II. LactotrophHeterogeneity ................................................................. A. Heterogeneity of prolactin molecule ..................................................... B. Anatomicheterogeneity .... .... .... ..... .... ..... .... .... ..... .... .... ..... .... .... ............................................................... C. Functional heterogeneity III. Cell-to-Cell Interactions: Paracrine and Autocrine Regulation of Prolactin Release ............ IV. Inhibitory Control of Prolactin Secretion ................................................... A. Dopamine ............................................................................. B. y-Aminobutyricacid .. .... ..... .... ..... .... ..... .... .... ..... .... .... .... ..... .... C. Somatostatin .......................................................................... D. Gonadotropin-releasing hormone-associated peptide ...................................... ........................................ E. Autoregulation by prolactin at level of lactotroph V. Prolactin-Stimulatory Factors ............................................................. A. Serotonin ............................................................................. B. Thyrotropin-releasinghormone ......................................................... ........................................................... C. Vasoactiveintestinalpeptide VI. Actions of Peripheral Hormones ........................................................... A. Estrogens ............................................................................. B. Catecholestrogens and exogenous antiestrogens .......................................... C. Other steroid hormones ... .... ..... ..... .... ..... .... .... ..... .... .... ..... .... .... D. Thyroidhormones ..................................................................... .................................. VII. Intracellular Mechanisms That Regulate Prolactin Release A. Pituitarycellsystems .................................................................. B. Adenylate cyclase and cyclic nucleotides ................................................. C. Phosphoinositide metabolism ........................................................... D. Arachidonate .......................................................................... E. Roleofcalcium ........................................................................ F. Phosphorylation of intracellular proteins ................................................ .................................. VIII. Mechanism of Action of Prolactin and Its Biological Effects ............................ IX. Implications for Abnormalities of Prolactin Secretion in Humans

I. INTRODUCTION

In the absence of direct nerve connections between the brain and the anterior pituitary gland, the unique arrangement of tuberoinfundibular dopaminergic (TIDA) neurons, which are anatomically associated with the hypothalamic portal vasculature in the median eminence, provides an important medium for the exchange of nervous and hormonal messages. The hypothalamus has been shown to exert predominantly inhibitory influences on prolactin (PRL) secretion, although there is also evidence for the presence of stimulatory factors. The direct effects of inhibitory and stimulatory hypothalamic factors on the lactotroph are modified by “peripheral” hormones that reach the anterior pituitary gland via the systemic circulation. These include estrogens, thyroid hormone, glucocorticoids, and cate0031-9333/90

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cholamines from the adrenal medulla. This “classic” scheme of the neuroendocrine regulation of PRL secretion must now be amended because of the heterogeneity of pituitary lactotrophs, both with regard to the characteristics of the PRL molecules they secrete under different conditions and to their anatomic and functional heterogeneity. In addition, the recently formulated concept of paracrine and autocrine regulation of PRL release at the level of the lactotroph provides new insights into the regulation of the “fine tuning” of PRL secretion under different physiological conditions. The intracellular mechanisms regulating PRL synthesis and release involve both the adenylate cyclase-adenosine 3’,5’-cyclic monophosphate (CAMP) and phosphoinositol pathways, systems where the activation seems to be differentially regulated. Recent evidence suggests that PRL may, at least partially, exert its biological effects via the formation of an intermediate trophic 279

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factor that could be synthesized outside the pituitary gland. The progress in our knowledge of the physiological regulation and function of PRL secretion has resulted in a dramatic increase in the clinical awareness and consequences of hyperprolactinemia in humans, whereas its effective treatment with dopamine agonists has resulted in virtual abandonment of surgical intervention in patients with PRL-secreting pituitary tumors. In the rapidly expanding field of neuroendocrinology, a considerable number of reviews on the regulation of PRL secretion have appeared in recent years (40, 126, 200, 381,407,444, 533, 652, 702, 730). II. LACTOTROPH

HETEROGENEITY

Most of our knowledge concerning the ontogeny, anatomy, and physiology of lactotrophs in the anterior pituitary gland was originally gained from studies using immunocytochemistry, electron microscopy, and radioimmunology to measure hormone concentrations in pituitary extracts, in the media of cultured pituitary cells, and in plasma samples. Immunocytochemistry and electron microscopy provide information about the presence of stored hormone within pituitary cells, whereas radioimmunoassay mainly concerns itself with the average contribution of all cells involved in the release of PRL. Neil1 and Frawley (535) initiated the use of another technique, the reverse hemolytic plaque assay, to measure hormones released by individual pituitary cells. This technique is based on the principle that hormone production by individual cultured pituitary cells can be assessed on the basis of complement-mediated lysis of erythrocytes coupled to an antibody that binds the secreted hormone. This results in a clear zone of hemolysis surrounding the cell. The size of this plaque reflects the amount of hormone released during the incubation period. The use of this method together with several new developments in electron microscopy, in separation techniques of pituitary cells, and in other methods for the investigation of single cell behavior have shed new light on the anatomy and physiology of PRL-secreting cells and suggest the existence of considerable heterogeneity in 1) the structure of the PRL molecule as it is released under varied conditions, 2) the development and anatomic distribution of lactotrophs throughout the pituitary gland, and 3) the functional behavior of lactotrophs. A. Heterogeneity

of Prolactin

Molecule

Human PRL consists of 198 amino acid residues (651). Its sequence identities with rat, pig, and sheep PRL are 60, 77, and 73%, respectively, whereas its sequence identities with human growth hormone and placental lactogen are only 16 and 13%, respectively. The molecular nature of the PRL gene, its structure, and the regulation of its expression have recently been extensively reviewed by Shull and Gorski (652). A com-

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mon tissue-specific transcription factor has been found for the activation of cell-specific expression of rat PRL and growth hormone (GH) genes (538). Such a common developmental signal for the activation of the GH and PRL genes concurs with observations that during pituitary development the appearance of somatotrophs temporally precedes that of lactotrophs, whereas virtually all progenitor PRL-producing cells show a transient coexpression of GH. Even in adulthood a certain percentage of mammosomatotrophs seems to remain present in the normal pituitary gland (see next section). Prolactin is not a single molecule but most likely consists of a family of molecular variants differing from one another in their biological and immunological potencies (23, 413, 557). Prolactin is synthesized on polyribosomes in the rough endoplasmic reticulum, initially as a precursor, and is cleaved before the native peptide is completed. Thereafter it is transferred to the Golgi zone where it is packaged into secretory granules. The rate of PRL synthesis and release is modulated by a variety of hormones and factors (see sect. III). The sequence of the intracellular events in PRL synthesis has been extensively studied by Farquhar and co-workers (186, 187), and several aspects of the synthesis and intracellular kinetics of PRL have been reviewed by Dannies (116). Both human and rat PRL exhibit a molecular heterogeneity by containing two molecular forms, designated as “big” and “small” PRL (94,211, 604, 680), that are associated with well-differentiated cytoplasmic pools in the rat (700). Small or monomeric PRL appears loosely coupled to organelles involved in the synthesis and processing of the hormone and is readily soluble in pituitary homogenates. Big or polymeric PRL is mainly stored in secretory granules, and depolymerization is needed to yield the monomeric radioimmunoassayable form (701). Recently a small-molecular-weight variant (21,000) of rat PRL was detected that consists of a cluster of proteins that are structural variants of PRL, raising the possibility that these variants result from alternative splicing of the PRL gene transcript (657). Glycosylated forms of PRL have also been identified in ovine (413), porcine (562), and human (415,494) pituitary glands. Glycosylated PRL is present in the serum of normal men and women, and its amounts may vary in certain physiological states, such as pregnancy (461,462). Its significance at present is unclear, but it is probable that glycosylated ovine PRL possesses less bioactivity than ovine PRL (414, 463). Analysis of PRL variants in the circulation suggests that different forms of PRL are preferentially released in response to different physiological and pathological stimuli (185, 216, 405, 410, 655). Considerable discrepancies have been noted with regard to measurements of the PRL content in the pituitary gland using different bioassay systems, disk electrophoresis, and radioimmunoassays after stimuli, such as suckling and mammary nerve stimulation, and also after cysteamine administration (242,490,540,619). The marked depletion in pituitary PRL stores in these cases is not


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always accompanied by a parallel increase in the secretion of PRL into the circulation. A two-phase PRL secretory process has been proposed in which it has been suggested that the PRL depleted during suckling does not escape from the pituitary gland but rather is largely transformed .into a structure that is potentially more releasable but no longer detectable by bioassay, disk electrophoresis, and/or radioimmunoassay (243-245, 490,540). In addition, the PRL form that is released into the circulation is also not always detectable by radioimmunoassay (656). In the pigeon crop assay (539) and in the rat lymphoma cell line (608, 647, 687), bioassay systems for PRL are based on the mitogenic actions of PRL. These mitogenic responses to rat PRL are also influenced by serum (513). Frawley et al. (208) have developed a bioassay system that measures casein production by mammary cells in culture using the reverse hemolytic plaque assay. This assay system, which has very high sensitivity, allows the investigator to evaluate the biopotency of PRL released from individual lactotrophs and, simultaneously, to determine the amount of immunoreactive PRL released using the hemolytic plaque assay. These investigators observed major differences among lactotrophs with regard to the bio- and immun opotency of PRL released from the same cell. The d ata presented th us far support the concept that there is cons iderable heterogene ity, not only in the molecular forms of PRL secreted by the anterior pituitary gland under variable physiological and pathological conditions but also in the biopotency of the PRL released. In addition, a cellular basis for this heterogeneity is suggested, although it is unclear whether there are s pecific subpo pulations of lactrotrophs, ea .ch of which release single variants of the PRL molecule, or whether all lactotrophs have the capacity to release multiple variants of PRL under different conditions. B. Anatomic Heterogeneity

Most studies on the ontogeny of GH- and PRL-containing cells of the anterior pituitary gland suggest that the appearance of GH cells precedes that of the PRL cells considerably. This has been shown in many species, including humans (30), rats (729), mice (660), and sheep (564). Virtually all morphological studies have detected a clear distinction between lactotrophs and somatotrophs within (fetal) pituitaries (30, 115, 677). However, immunocytochemical studies of the pituitaries of day 21 rat fetuses have suggested the presence of a small category of cells that contain both GH and PRL (93). Dynamic studies by Strattmann et al. (678) have also indicated that there may be an ontogenic interconversion of GH and PRL cells within fetal rat pituitaries, because estrogen-exposed soma totrophs acquire the ultrastruc tural characteristics of mammo trophs. By combining the reverse hemolytic plaque assay with immunocytochemistry, Hoeffler et al. (272) found PRL cells to be extremely rare in the cultured pituitary

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of day 18-21 rat fetuses, whereas they first appear in appreciable numbers in 4-day-old animals. In a study of 5-day-old rats, the number of PRL cells constituted 10% of the total pituitary cells, whereas a peak percentage of GH-secreting cells was ~40%. Using a sequential reverse hemolytic plaque assay, which enables detection of both PRL and GH release from the same cells, Hoeffler et al. (272) found that for every 100 pituitary cells that release PRL and/or GH, 62 release GH only, 2 release PRL alone, and 36 release both PRL and GH. These findings were confirmed by double immunohistochemical staining of these cells. These results indicate that mammosomatotrophic cells, which release both GH and PRL, appear early in the neonatal development of rats, while suggesting that PRL-secreting cells arise from a progenitor GH-secreting cell. The existence of mammosomatotrophs in normal fetal pituitaries and their persistence into the adult pituitary glands of several species has been shown by using the sequential reverse hemolytic plaque assay and double immunocytochemistry at the electron-microscopic level. In the latter technique, PRL and GH are both labeled with different sizes of colloidal gold bound to a second antibody (529). The percentages of mammosomatotropic cells detected by investigators in the anterior pituitary of adult normal male rats has ranged from as much as 33% (206) to as little as 5% (408) and even none at all (537). Neil1 et al. (537) have delineated several aspects that limit the use and interpretation of the reverse hemolytic plaque assay. Apart from the possible artifactual presence of plaques in the second sequence of the assay, differences in GH and PRL that are measured by this assay procedure should be interpreted with caution because of the number of molecular forms of both GH and PRL, making the choice and characteristics of the antisera used in these assays of great importance. Nevertheless, studies using ultrastructural immunocytochemistry with double immunogold labeling also suggest the presence of a subpopulation of mammosomatotrophs in normal adult male and in cycling and lactating female rats (546) as well as in cows (214). With the use of the reverse hemolytic plaque assay to monitor PRL and GH secretion from individual human fetal pituitary cells, a subpopulation of cells obtained from 180 to 22-wk-old fetuses was shown to secrete both PRL and GH (514). The same technique yielded a measurement of 26-50% mammosomatotrophs in adult human pituitaries (423). The presence of mammosomatotrophs in fetal and in early neonatal life and their persistance into adulthood in several species may be significant to an understanding of the physiology and pathology of PRL and GH secretion. The fetal mammosomatotroph may be a progenitor cell for PRL cells or an intermediate phase within the conversion of GH- to PRL-secreting cells. The persistance of these mixed GH/PRL-secreting cells into adulth ood may partially explain the fu nctional h eterogeneity of PRL-secreting cells in their responses to different stimuli, as discussed in the next section. Mammosomatotrophs are also present and/or persist in


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many human pituitary tumors (261, 281, 747). At least one-third of cultured pituitary tumor cells obtained from acromegalic patients secrete both GH and PRL (380). Often this is reflected by the presence of hyperprolactinemia in these patients. The clinical significance of these observations is that GH secretion by mixed GH/PRL-secreting tumors generally shows a greater sensitivity to the inhibitory effect of the dopamine agonist bromocriptine, whereas PRL release by mixed GH/PRL-secreting tumors displays more of a sensitivity to the inhibitory effect of the somatostatin analogue SMS-(201-995) (380,401). This suggests that mammosomatotropic tumor cells have retained receptors for the respective, normal physiological inhibitory regulators of PRL and GH release, dopamine and somatostatin. C. Functionul

Heterogeneity

In studies using double-isotope hormone labeling, Walker and Farquhar (724) showed that newly synthesized PRL is preferentially released during spontaneous hormone secretion from cultured normal rat pituitary cells. The existence of fast and slow releasable PRL pools within the same cell or between different subpopulations of lactotrophs was further substantiated by the observation that thyrotropin-releasing hormone (TRH) preferentially stimulated the release of older stored PRL without affecting the release of newly synthesized hormone. Studies on the possible functional heterogeneity of lactotrophs have been hampered by the presence of at least six distinct pituitary cell populations that secrete different hormones. Apart from the reverse hemolytic plaque assay, several techniques have been developed to prepare enriched lactotrophic cell populations or to study the functional dynamics of individual pituitary cells. These techniques are based on differences in cell characteristics, such as sedimentation velocity (150, 289), light scattering (263), or cell surface antigens (675). In addition, immunofluorescence (690) and cell blotting (341) have been used to further delineate the existence of subpopulations of functionally different lactotrophs. Prolactin-secreting cells, recovered from different sedimentation fractions, secrete different amounts of PRL (662). Through the use of a discontinuous Percoll gradient, Velkeniers et al. (713) were able to purify PRL cell populations that exhibit differing amounts of hormone and responses to provocative stimuli. Low-density PRL cells secrete large amounts of hormone, whereas lactotrophs with high density are heavily granulated and have lower secretory capacity and transcriptional activity. The population of PRLenriched cells responds to dopamine and to vasoactive intestinal peptide (VIP) in the same manner as an unseparated cell suspension. Estrogen-induced hyperplastic and tumorous lactotrophs and the GH3 cell line are composed of morphologically and functionally heterogeneous cell populations. with individual cells secreting

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varying amounts of PRL in the basal state and displaying varied reactions to TRH and cortisol (61, 264, 288, 424). Interestingly, mammosomatotrophs have been detected within the GH3 cell line (63). With the use of the reverse hemolytic plaque assay, it has been observed that many normal lactotrophs barely respond to TRH (62), whereas subpopulations of lactotrophs show varied responses to dopamine (207). Dopamine preferentially inhibits PRL release from cells with elevated basal secretory rates (439). Monitoring of the cytosolic free calcium concentration in single rat lactotrophs also showed evidence of the heterogeneity of these cells with respect to their responses to TRH and dopamine (737). It is unclear at present whether variations in the sensitivity of lactotrophs to TRH and dopamine indicate any presence of different populations of “pure” lactotrophs and mammosomatotrophs within the normal pituitary gland. Indeed, hypothalamic factors appear to have the capacity to induce differential effects on the proportions of GH- and PRL-secreting cells within the pituitary gland (273). The existence of functional variations among lactotrophs from different pituitary regions has been documented by Boockfor and Frawley (60). In a study of day 10 lactating rats, lactotrophs from the peripheral rim (outer zone) of the anterior pituitary showed a high sensitivity to TRH and only a moderate sensitivity to dopamine. However, PRL release by lactotrophs from the central region (inner zone) of the pituitary was markedly inhibited by dopamine and only slightly increased by TRH. The outer zone of the pituitary gland contained a larger proportion of mammosomatotrophs than the inner zone. Functional heterogeneity among lactotrophs located in different regions of the anterior pituitary gland can be further substantiated by two previous studies. Papka et al. (563), using immunoperoxydase and immunogold labeling techniques, showed two distinct areas of concentrated lactotrophs in the pituitaries of lactating rats: a narrow peripheral rim (outer zone) and a larger, more centrally located region (inner zone). Reymond et al. (601) found that blood in the central portal vessels contains higher dopamine concentrations than the more peripherally located vessels of the hypophysial stalk of male rats. In conclusion, these studies suggest the existence of functionally different lactotrophs in the normal pituitary gland. It should be kept in mind, however, that the data supporting these suggestions have been obtained using a variety of techniques, including morphological studies, cell separation, and the use of the reverse hemolytic plaque assay. At the single cell level, experimental approaches usually rely on a single parameter of discrimination, e.g., immunocytochemistry (stored hormone) or plaque assay (released hormone). Leong et al. (408) has commented that “these aspects are unlikely to be common among all cells of a given class. For example, a cell distinguished by immunocytochemistry as storing a hormone may not export that hormone and permit identification by hemolytic plaque assay. The converse mav also hold: some proteins that are consti-


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tutively exported may not be concentrated within secretory granules, making detection by immunocytochemistry difficult. Thus no single technique can serve as a standard for comparison.” III.

CELL-TO-CELL AUTOCRINE

INTERACTIONS: REGULATION

PARACRINE OF PROLACTIN

AND RELEASE

It has become clear in recent years that several communication systems exist in endocrine tissues in which hormone-secreting cells produce messengers that affect either the cells, their own secretory activities (autocrine regulation), or those of neighboring cells (paracrine regulation) (for reviews see Refs. 409, 671). Denef and co-workers (144, 145, 148) have provided strong evidence that such cell-to-cell interactions play a role in the normal regulation of PRL release. In what can be called classic studies, Denef showed that gonadotropin-releasing hormone (GnRH), which has no direct effect on PRL release by lactotrophenriched cell populations, stimulates this release if the cells are cocultured (reaggregated) with gonadotrophin-enriched cell populations. The presence of gonadotrophs thus appears essential for GnRH-stimulated PRL release to occur (143, 144, 146). In addition, medium removed from gonadotroph-enriched cell cultures also stimulates PRL secretion (146). This first example of a paracrine effect of GnRH-stimulated gonadotrophs on lactotrophs, which could only be demonstrated in pituitary cells obtained from 14-day-old rats, may help to explain the topographically close association and even junctional connections between these two cell types within the rat pituitary gland (280,548,618). Indirect support for the existence of such a paracrine factor originating from luteinizing hormone (LH)-secreting cells has been obtained from in vivo experiments with GnRH analogue-induced PRL secretion (392). A second example of paracrine modulation of PRL release was provided by observations from Denef’s group. Angiotensin II (ANG II) stimulates PRL secretion in vivo as well as basal and dopamine-inhibited PRL release by cultured normal rat pituitary cells (4, 560, 633, 634, 672). The response of enriched lactotroph populations to angiotensin II can be considerably increased by reaggregation with gonadotroph-enriched cell populations. Preliminary evidence suggests that other pituitary cell types (e.g., thyrotrophs) may also be involved in the regulation of PRL release by ANG II through a paracrine mechanism (145, 148, 149). Angiotensin II is present within the normal pituitary gland (151), although there are also ANG II receptors on lactotrophs (4, 633). Angiotensin II exerts a stimulatory effect on PRL release in vitro that may be more potent than that exerted by TRH or vasoactive intestinal peptide (VIP) (83, 179, 633, 634). Angiotensin II promotes PRL release from normal human pituitary cells (457), an action that probably involves stimulation of polyphosphatidylinositol breakdown (83, 179, 310). Estradiol exerts a direct inhibitory action on the expression

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of pituitary ANG II receptors, but this is not accompanied by a decrease in the ANG II-mediated stimulation of PRL secretion (576). A third example of paracrine mechanisms involved in the regulation of PRL release is the observation that the stimulatory effect of ,C?-adrenergic catecholamines on PRL secretion is clearly seen in superfused pituitary cell aggregates with cell-to-cell interactions but not in superfused or cultured dispersed normal pituitary cells (27, 147, 568). This suggests that ,B-adrenergic stimulation of PRL release is not mediated via a direct effect on the lactotroph but rather needs an intercellular messenger system (145, 148). Recently, the first firm evidence was presented for an autocrine control mechanism in the regulation of PRL release (254, 525, 598). Vasoactive intestinal polypeptide previously had been shown to stimulate PRL release in vivo and in vitro (1, 175, 210, 334, 607, 718). The view held that VIP, originating from the hypothalamus, is transported via the portal blood system to the pituitary gland, where it stimulates PRL release after activating the adenylate cyclase system via specific VIP receptors (see sect. v). However, VIP is also present and probably synthesized within the anterior pituitary gland, specifically within lactotrophs (21, 49, 507, 545). Hagen et al. (254) reported anti-VIP antiserum reduced basal PRL release from nonstimulated cells and raised the possibility that VIP, in addition to its role as a hypothalamic-derived PRL-releasing factor, may also regulate PRL release via an intracellular mechanism. Nagy et al. (525) have recently presented evidence that locally produced VIP acts in an autocrine fashion as a stimulator of PRL release. They have shown that VIP antibodies and a VIP antagonist profoundly (but reversibly) suppress PRL secretion in primary cultures of rat pituitary cells. These studies were carried out using the reverse hemolytic plaque assay in which PRL release from individual lactotrophs is observed without cell-tocell interactions. Observations suggesting an autocrine regulatory aspect could be additive or modulatory to the effect of the hypothalamic-derived VIP may help clarify previously unexplained observations in which several neuropeptides, shown to stimulate PRL release in vivo, were also detected by immunocytochemical techniques within the anterior pituitary gland. In addition to ANG II and GnRH (509), these substances include substance P (508,717), neurotensin (NT) (174,231,717), and secretin (614). It is unclear at present whether the immunocytochemical identification of these peptides within the pituitary gland represents their local synthesis or only their uptake from the portal circulation. At present no proofs for autocrine and/or paracrine effects of these latter substances on PRL secretion have been offered (145, 148, 525). Further studies that suggest autocrine or paracrine mechanisms in the regulation of PRL release are those by Morel et al. (510), who presented immunocytochemical evidence that TRH in the rat is internalized into pituitary target cells. In this respect, it is unclear


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whether His-Pro-diketopiperazine, a metabolite of TRH formed within the hypothalamus and the pituitary gland, exerts a physiologically important role at the lactotroph as an inhibitor of PRL release (39, 399). Other potential paracrine stimulatory or inhibitory factors of PRL release that are SYn thesized and/or present in the normal pituitary gl and are ,&endorphin and several of its fragments, including y-type endorphins (99, 178, 378). Also the catecholestrogens 2-hydroxyestradiol and 2-hydroxyestrone, which are locally formed within the pituitary gland from estradiol, may influence PRL release via such a paracrine effect (see sect. VI). Another interesting aspect of an autocrine and/or paracrine regulation of PRL secretion is the observation that the anterior pituitary gland synthesizes and probably secretes a variety of polypeptide growth factors (see Refs. 145, 521). Epidermal growth factor, which is synthesized by the normal pituitary gland (371), stimulates PRL synthesis and release (307, 519, 632,742). Insulin-like growth factors are synthesized in the pituitary gland (53) and decrease (233) or more consistently stimulate PRL release (744). Pituitary folliculostellate cells have been shown to synthesize and secrete fibroblast growth factor (192), which stimulates PRL synthesis (28). The role of the folliculostellate cells in the anterior pituitary gland has been recently investigated by Baes et al. (26), who suggested that these cells may contribute to the intercellular messenger system, primarily by producing inhibitory paracrine factors involved in the control of pituitary hormone (including PRL) secretion. Recently Friesen and Vrontakis (212) and Vrontakis et al. (722) presented evidence indicating that some part of the multiple actions of estradiol on lactotrophs may be mediated by a locally synthesized growth factor. Sequence analysis of a cDNA clone isolated from an estrogen-induced pituitary tumor cDNA library identified a 124-amino acid protein that is 70% identical to the porcine galanin precursor protein. Consisting of 29 amino acids, galanin (glycine ending with alanin) was originally isolated from the small intestine of the pig (688). Galanin stimulates both GH and PRL secretion in the rat; its action on PRL release apparently occurs via a hypothalamic effect, resulting in increased VIP release and/or decreased dopamine release into the portal system (366, 488, 549). Galanin is also synthesized within the pituitary gland, probably in lactotrophs (212). Preliminary evidence thus suggests that galanin may contribute to the proliferation of lactotrophs by acting as an estrogen-dependent growth factor that transmits its actions via a paracrine or autocrine action (212, 722). The concept of autocrine regulation may also apply to dopamine. Early experiments from Porter and collaborators showed that subsequent to dopamine’s binding to its receptors, it is internalized in the lactotroph (247, 605), and an association between intracellular dopamine and PRL secretory granules (530) and lysosomes (605) has been observed. The uptake of dopamine

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into lysosomes may contribute to increased lysosomal enzyme activity (531), resulting in an enhanced degradation of PRL (117), but the association of dopamine with PRL within secretory granules may well result in an autocrine-mediated inhibitory action of dopamine as soon as a secretory granule releases its hormone together with dopamine. In conclusion, a variety of studies provides evidence that cell-to-cell interactions are involved in the regulation of normal PRL secretion. At present there is firm evidence only for the existence of paracrine regulatory factors that originate from gonadotrophs, folliculostellate cells, and possibly thyrotrophs, in addition to an autocrine regulatory role for VIP synthesized in the lactotroph. In addition, a variety of neuropeptides and locally synthesized growth factors also affect PRL synthesis and release via these mechanisms. Prolactin is unique among hormones of the anterior pituitary gland in that its secretion is “spontaneous”: in the absence of hypothalamic or hypophysiotropit influences, lactotrophs secrete PRL at a high rate (see Refs. 40,407, 525). Indeed, rapidly fluctuating PRL levels can be observed in the serum of hypophysectomized male rats bearing isografts of pituitary tissue (646). Prolactin pulsatility is amplified by blockade with dopamine receptor-blocking drugs (644), whereas the pulse magnitude is amplified by estradiol (646). Monkey hemipituitaries perfused in vitro also show a pulsatile release of PRL (673). The intrinsic pulsatility of PRL secretion, which obviously originates for the greater part from within the pituitary gland, could well represent in part the result of different paracrine and autocrine activities within this gland. IV.

INHIBITORY

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SECRETION

The anatomic connection between the median eminence and the anterior pituitary gland is critical to maintaining the physiological control of PRL secretion. Pituitary stalk section, the placement of electrolytic lesions in parts of the median eminence, and the transplantation of the pituitary gland beneath the kidney capsule all induce long-lasting hyperprolactinemia and increased pituitary PRL stores (55,95,183,452). Several hormones and substances have been shown to exert direct suppressive effects on PRL release, with dopamine as the main inhibitory regulator (444). A. Dopamine

In vitro studies using rat hemipituitary glands showed that PRL secretion is inhibited by adding catecholamines, particularly dopamine, to the culture medium (54, 443, 446, 453). Dopamine is a more powerful inhibitor of PRL release than norepinephrine. The specificity of the dopamine effect is readily apparent, because dopamine receptor-blocking agents, such as haloperidol, overcome dopamine’s effect in a dose-depen-


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dent manner (444, 450, 453). In additional studies the inhibitory effects of ergot derivatives were found to be mediated through the same mechanisms (444,452,453). The use of hemipituitary glands and/or dispersed cultured or superfused rat pituitary cells to measure PRL release has subsequently been used in the development of new ergot derivatives that can be used clinically in the control of hyperprolactinemia and in the investigation of the mechanism of action of this type of drug (197-199, 387, 745). In the initial years after these discoveries, some doubt was raised about the direct inhibitory effect of dopamine on PRL release. These questions may have been caused, at least in part, by the fact that culture mediums containing high concentrations of bicarbonate attenuate the inhibitory effects of dopamine (386). Dopamine receptors with a high affinity for dopamine and its analogues have been identified on rat, bovine, and human pituitary tissues, whereas no such receptor sites have been identified in the basal hypothalamus (70, 92, 107, 112, 592). There appear to be two classes of dopamine binding sites, of which the high-affinity site is in all likelihood the biologically active site with a dissociation constant (Kd) of 4.4 X 10-l’ M. The dopamine receptor on the pituitary gland has been designated a D2 receptor (for reviews see Refs. 40,201). Stimulation of the TIDA neurons results in the secretion of dopamine into the hypophysial stalk serum because of these neurons’ close anatomic association with the hypophysial portal vessels (15, 275). The concentration of dopamine in the hypophysial stalk circulation is much greater than that in the systemic circulation (230). Several studies have shown that stalk serum dopamine concentrations are, in physiological circumstances, inversely related to peripheral PRL concentrations (42, 577), although this relationship is not considered sufficient to explain the changes in circulating PRL levels (124, 125, 127). Data obtained with portal stalk blood cannulations have been extensively reviewed (40, 126). The TIDA system has cell bodies in the arcuate nucleus and short axons that terminate in the median eminence (for reviews see Refs. 505,506). In contrast to the nigrostriatal dopaminergic system, the TIDA system is not directly regulated by dopamine receptor-mediated mechanisms (506). Instead, it is stimulated by implanted, systemically, and intracisternally administered PRL (16, 246, 276, 308, 567, 721). Indeed PRL is present in normal conditions in the cerebrospinal fluid where its concentration roughly correlates with that found in the systemic circulation (435). Estrogens exert a powerful action on tuberoinfundibular neuron activity, with the sexual difference being reflected in a two to three times greater activity in female than in male rats (139). The dopamine concentration of pituitary stalk blood was shown to be severalfold higher in the female rat (41, 42, 249). Pronounced changes in TIDA neuron activity were detected early on the day of proestrus by measuring the 3,4-dihydroxyphenylacetic acid (DOPAC)-to-dopamine ratio and tyrosine hydroxy-

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lase activity in the median eminence (565). At the prescribed time of increase in plasma estradiol levels, a reduction in the bioamine ratio and enzyme activity occurred, which correlated with the proestrus surge in PRL. These findings support the classic view that TIDA neurons exert a tonic inhibitory action on PRL secretion. The TIDA system is inhibited by afferent neuronal circuits that are activated by lactation, suckling, and restraint stress (137, 140). It is noteworthy that blind, anosmic rats have reduced serum PRL levels and an increase in hypothalamic dopamine turnover (406). The associative changes in TIDA neuron activity and in serum PRL levels were highlighted by the finding that hypoprolactinemia, induced by hypophysectomy or bromocriptine treatment, decreased TIDA activity as measured by 3,4=dihydroxyphenylalanine (DOPA) accumulation in the median eminence (140, 142). A similar effect of neonatal PRL deficiency on TIDA activity was observed (653). This study showed that the dopamine turnover in the median eminence was decreased in pups nursed by bromocriptine-treated lactating rats. Aside from a feedback effect of peripheral PRL on the activity of the hypothalamic tuberoinfundibular system, a multitude of neurotransmitters and neuropeptides have been implicated in affecting the amount of dopamine released into the portal circulation and/or stimulating simultaneously the release of hypothalamic PRL release-stimulating factors (see sect. v). In this regard, certainly the chronic tonus of dopamine is responsible for the basal levels of plasma prolactin that are usually detected. During periods of physiological stimulation (suckling) or endogenous or exogenous artificial enhancement of circulatory PRL levels, however, the coordinated actions of stimulatory factors seem to be coupled to a transient interruption of the dopaminergic inhibition (41, 123, 125, 127). An in vitro model of this situation recently showed that in cells cultured with dopamine for 24 h an abrupt withdrawal of the inhibitor stimulated PRL release to levels observed in cells cultured in medium not containing dopamine, i.e., -95% higher than control values (474). More importantly, the transient removal of dopamine from the incubation medium resulted in a much greater stimulation caused by adding TRH than was observed when TRH was added to cells not chronically inhibited by dopamine. Accompanying changes in second messenger components were also documented. Opiates are a class of neurotransmitters that exerts a powerful influence on PRL secretion. Both morphine and ,&endorphin stimulate PRL release (167, 486), whereas naloxone attenuates these effects (190, 711) and possibly possesses a weak PRL-inhibiting effect on its own (464,620). The recent findings of Krulich et al. (369) show that bremazocine and U 50488, selective K-opioid receptor activators, are potent in vivo stimulators of plasma PRL. This stimulatory effect was highly resistant to antagonism by naloxone and indicates that central K-opioid receptors also have an important function in the regulation of PRL release. In a related study, it was found that pretreatment of rats


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with hydrocortisone moderated the stimulatory action of U 50488 and other opioids on PRL release. The effect of hydrocortisone was largely negated by actinomycin D (343). Endogenous opiates probably play an important role in the regulation of stress-induced PRL secretion (712); recently, peripheral catecholamines have been implicated in this as well (696). The effects of endogenous opiates are mainly mediated by an inhibition of the synthesis and release of dopamine by the tuberoinfundibular system (9, 20, 190, 600, 711). Another hypothalamic substance that may affect PRL release via changes in the dopaminergic activity is serotonin (72, 138; see also sect. v). The mechanisms of action of histamine (416)-, acetylcholine (240)-, oxytocin (615)-, substance P (603)-, and NT (603)-stimulated PRL secretion are still largely unknown. An intriguing addition to the rather simple concept of a hypothalamic dopaminergic inhibitory control of PRL secretion is the suggestion that the posterior pituitary lobe may participate in determining the final concentration of dopamine acting at the lactotroph. Ben-Jonathan (40) developed this concept and reviewed it in detail. Most of the axons of the neurons of the arcuate nucleus end in the median eminence, but some are directed to the posterior lobe (58). Dopamine can reach the anterior pituitary lactotrophs from the posterior lobe via the short portal vessels (559). Posterior pituitary lobectomy in rats under different physiological conditions results in a sustained elevation of plasma PRL levels (43,213,516). Murai and Ben-Jonathan (517) showed that posterior pituitary lobectomy in lactating rats completely abolishes the suckling-induced rise in plasma PRL. The fact that the hypothalamic dopamine system is functioning properly in these rats is indicated by the observation that a-methyl-p-tyrosine administration caused a prompt increase in plasma PRL. The functional integrity of the hypothalamic serotonergic system as it relates to PRL release was also demonstrated. In summary, these data suggest that the dopaminergic inhibition of PRL release involves two or perhaps three interdependent systems. Two systems consist of the transport of dopamine via the hypothalamic long and posterior pituitary short portal vessels from the median eminence and the posterior lobe, respectively, whereas a third system may be an autocrine inhibitory effect caused by the direct release of previously internalized dopamine at the level of the lactotroph (see sect. III). It is unclear at present as to what physiological, hormonal, or neuronal stimuli may be activated by one of these three systems. The possible role of the posterior pituitary lobe in the regulation of PRL secretion has become more complex, because evidence has been presented that this tissue contains a PRL-releasing factor (517). More recent data from this laboratory indicated that perifusion of dispersed pituitary cells with small quantities of posterior pituitary extract promoted a selective increase in PRL release that was much greater than that produced by hypothalamic extracts and that PRF is not one of the previously identi-

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fied stimulatory factors (286). The origin of this posterior pituitary PRF is hypothalamic, because stalk sections of rats caused its disappearance from the distal section (285, 287). The researchers speculate that this PRF may be synthesized in cell bodies in the paraventricular nucleus and transported to the posterior pituitary in th e same manner as other neurohypophyseal horm ones. B. y-Aminohtyric

Acid

y-Aminobutyric acid (GABA) has also been shown to be involved in the regulation of PRL secretion. Interestingly, it appears to have a dual and in fact opposing role in this regulation. At very high concentrations GABA exerts a direct inhibitory effect on PRL release by the pituitary gland in vitro (384, 591, 622), an effect apparently mediated via specific GABA receptors (239). Several studies support the evidence for pituitary GABA receptors and further suggest that GABA’s ability to inhibit PRL release may be related to an alteration in the GABA receptor-chloride channel complex (13, 18). Additional studies suggest that GABA may inhibit PRL release from bovine lactotrophs by activating Cl- channels, which appear to be voltage dependent (291, 292). The earlier report in inhibition of PRL synthesis by Lamberts and MacLeod (384) was recently expanded by the studies of Loeffler et al. (428), who showed that GABA and its agonists decrease PRL mRNA accumulation in cultured rat pituitary cells, thus suggesting that GABA exerts inhibitory actions on secretion and gene expression. Porcine median eminence extracts contain GABA, which has been implicated in the inhibitory control of PRL secretion (622) via either specific tuberoinfundibular GABAergic pathways (719) or by modulation of the dopaminergic system (17). In contrast, intracisternally administered GABA stimulates PRL secretion (427). Ondo and Dom of muscimol, a (554) demonstrated that a microinfusion GABA agonist, into the arcuate nucleus (but no other hypothalamic area) significantly increases plasma PRL levels, thus supporting the contention that GABA may regulate PRL release via the TIDA system. In a related study, Lux et al. (440) reported that baclofen, a GABAB agonist, did not modify circulating PRL levels in rats with lesions in the median eminence. The frequent and pulsatile release of GABA from the mediobasal hypothalamus of ovariectomized rats, measured via pushpull cannula methodology, was profoundly reduced by estradiol administration (304, 305). The authors concluded that enhanced circulating PRL levels in estradiol-treated rats may involve estrogen-receptive, GABAergic neurons in the medial basal hypothalamus. The existence of a feedback mechanism involving the direct action of PRL at the hypothalamic level was demonstrated by the finding that the hormone decreased in vitro GABA concentrations and increased GABA release into the incubation medium (168,169). Relatively low GABA concentrations have been found in the hy-


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pophysial stalk plasma from diestrous rats, and these levels were similar to those found in the systemic circulation (515). C. Somatostatin

It was previously shown that somatostatin directly inhibits basal and stimulated PRL release by rat hemipituitaries and cultured pituitary cells (158, 191, 262, 374, 707). The presence of estradiol is essential for somatostatin to inhibit PRL secretion: estradiol directly regulates the sensitivity of the lactotroph to somatostatin by increasing the number of its receptors on these cells (348). Prolactin release by normal rat pituitary cells that were cultured in estrogen-free conditions (estrogen-stripped fetal calf serum in the absence of phenol red) is largely refractory to somatostatin (274). The addition of 1 nM estradiol to the culture medium restores the sensitivity l,OOO-fold (400). In this respect it should be noted that estrogens exert an opposite action on the sensitivity of the lactotroph to dopamine (596; see sect. VI). We showed with different estradiol concentrations that submaximal concentrations of dopamine and somatostatin exert an additive inhibitory effect on PRL secretion in vitro, whereas the inhibitory effect of the combination of both compounds remains the same, irrespective of estradiol concentrations (400). These data indicate that in the presence of increasing estradiol concentrations, the sensitivity to dopamine exhibited by the lactotroph decreases, whereas the sensitivity to somatostatin increases to the same extent. These observations may have physiological significance, because the concentrations of somatostatin that inhibit PRL release in vitro are well within the range of those present in the portal circulation (100). Estrogen-induced hyperprolactinemia in male rats can be effectively suppressed by somatostatin and its analogues (104, 331,348). Only marginal effects of somatostatin infusion (105) or no effects of its analogue Sandostatin (421) were observed on basal and TRH-stimulated PRL secretion in humans. However, if somatostatin was infused to estrogen-treated agonadal subjects, a highly significant inhibitory effect was exerted by the peptide on circulating PRL levels (235). The importance of estrogens may underlie the unexpected observations that stimulation of the hypothalamic periventricular nucleus or injection of somatostatin into male rats significantly enhanced the ability of VIP to increase PRL release (497). D. Gonadotropin-Releasing Hormone-Associated Peptide

Gonadotropin-releasing hormone-associated peptide (GAP) is a peptide, consisting of 56 amino acids, that has been characterized and synthesized as part of the human GnRH precursor molecule (547). It is pronorted that GAP is a potent inhibitor of PRL secretion.

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while simultaneously stimulating the release of gonadotropins in rat pituitary cell cultures. Initial studies showed that 10-l’ M GAP maximally inhibited PRL release by %45%, making this peptide more powerful than dopamine. Active immunization of rabbits with peptides corresponding to GAP sequences greatly induced increased PRL levels in serum (547), and GAP was immunocytochemically shown to be present in the rat median eminence (570). Unfortunately, the prolactin-lowering effect of GAP is not widely acknowledged. Schally et al. (621) reported that synthetic GAP did not inhibit PRL secretion in rats either in vivo or in vitro, while the first 13-amino acid sequence of GAP did not influence PRL secretion in vitro despite its persisting stimulatory effect on gonadotropin release (499). Also GAP did not affect PRL release by cultured human prolactinoma cells (296). It took several years before confirmation of some of these effects were presented. McCann and co-workers (746) recently reported that in vivo administration of GAP inhibits PRL release in rats in a variety of stimulatory conditions, including lactation and ether stress. These results suggest the possibility that GAP might be a hypothalamic peptidergic PRL release-inhibitory factor, the existence of which was previously hypothesized by several groups of investigators (152, 342, 372, 481, 502, 683). The effects and potential regulatory roles of several other hormones and substances that directly inhibit PRL release at the pituitary level are discussed in section III (the His-Pro-diketopiperazine metabolite of TRH) and in section VIB (the catecholestrogens). Recently, it was shown that intraventricular administration of atria1 natriuretic factor also inhibits PRL secretion, but its mechanism of action probably involves interaction with the hypothalamic dopaminergic system (613). E. Autoregulation

by Prolactin

at Level of Lactotroph

In vivo experiments with PRL-secreting pituitary tumors have shown that hyperprolactinemia results in decreased PRL content in the pituitary glands of tumor-bearing animals (98,385,455). Administration of exogenous PRL indicates a negative autoregulatory effect of PRL on its own synthesis and release at the pituitary level (617, 658). However, contradictory results have long questioned whether the site of action for this autoregulation is the pituitary gland, the hypothalamus, or both (3, 98, 487, 670). Despite the fact that specific PRL receptors are present in the pituitary gland (204), studies of direct effects of exogenously administered PRL on its own secretion in vitro have yielded equivocal results: a decrease in PRL release (266) and no effect (714, 720). However, recent studies using the reverse hemolytic plaque assay (207) and an in vitro system in which the medium was changed at ZOmin intervals (44) show that PRL exerts an autoregulatory role on its own secretion at the pituitary level. It is unknown, nowever, wnat pnysiological signincance 1

1

1

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1

l

1

.

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these observations hold against a background of convincing in vivo studies demonstrating a hypothalamic effect of PRL, i.e., stimulating dopamine turnover and its secretion by the hypothalamic tuberoinfundibular system. V. PROLACTIN-STIMULATORY

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5-hydroxytryptophan-induced (and restraint and ether stress induced) increase in PRL secretion (501). Intraventricular administration of serotonin causes a decrease in the dopamine concentration (572) and increases in the TRH and VIP levels of the portal blood (311, 642).

FACTORS

B. Th yrotyopin-Releasing Acute stimulation of PRL release occurs in the rat on the afternoon of proestrus, during suckling, and in response to different forms of stress. The mechanism of the acute stimulation of PRL secretion in response to suckling and stress conceivably could result from the transient decrease in the release of hypothalamic factors, notably dopamine, into the portal system. However, it is more likely that specific, as yet unidentified, PRL-stimulatory factors play a major role. Early studies showed that crude extracts of hypothalamic tissue contain factors that stimulate PRL secretion (66, 255, 709). In addition, stress further increases circulating PRL levels in rats in which the dopamine receptors are blocked or in which the catecholamines have been depleted (368, 645, 710). Extensive studies in the area of PRL-releasing factors suggest the existence of at least three physiologically active substances, serotonin, TRH, and VIP, each of which possesses distinctly different mechanisms of action in stimulating PRL secretion. A. Serotonin Data supporting the concept that serotonin stimulates PRL secretion were obtained from experiments in which large amounts of serotonin or its precursors 5hydroxytryptophan and tryptophan were administered (72, 97, 329, 365, 437). Similar effects of these amino acids have been observed in humans (335, 442, 740). Studies with serotonin receptor-blocking agents were not always conclusive (449, 370). Some of these compounds, such as metergoline, also have powerful dopaminergic activities (387); methysergide has antidopaminergic activities, whereas its metabolite, methergine, is a dopamine agonist (381). Cyproheptadine directly inhibits PRL synthesis and release by the pituitary gland in a nonserotonergic, calcium-dependent manner (383, 398). Serotonin does not directly stimulate PRL release by normal rat pituitary glands incubated in vitro (387); however, it does stimulate PRL secretion in hypophysectomized adenohyophyseal-grafted rats (676). Johnston et al. (309) clearly demonstrated the requirement of an intact neurointermediate pituitary lobe in order for 5-hydroxytryptophan administration to increase serum PRL levels. Evidence suggests that serotonin may act at specific receptors in the arcuate nucleus as a hypothalamic neurotransmitter involved in the stimulation of PRL release (735,736). However, the essential role of the paraventricular nucleus was shown in the

Hormone

Thyrotropin-releasing hormone induces PRL release by a direct action at the pituitary gland, and it is present in the hypophyseal stalk blood in higher concentrations than in peripheral blood (127, 268, 640). In humans a dissociation of PRL and thyrotropin secretion was observed during breast feeding (218). Several studies in rats, however, strongly suggest that TRH is involved in suckling-induced PRL secretion and probably also in the PRL surge in proestrous rats (125-128,135, 136, 243). The acute increase in TRH secretion was shown to be accompanied by a short-lived decrease in dopamine levels in the portal blood (126, 127). C. Vasoactive Intestinal

Peptide

Several lines of investigation support the contention that VIP exerts a stimulatory function on PRL release. Direct stimulatory effects of VIP on PRL release by lactotrophs via specific receptors have been demonstrated (1, 37, 57,175, 210,237, 334,375,497, 607, 612, 616, 638, 641, 718). Similar stimulatory effects of VIP have been reported on the in vitro release of PRL by prolactinomas (665), on PRL secretion by patients with microprolactinomas (103), and on secretion by pituitary tumor tissue in vitro (584). In one study such an effect was not observed (327). According to Opel and Proudman (555), the intraatria1 administration of VIP to turkeys promoted doserelated increases in circulating PRL levels in intact and ovariectomized birds as well as in birds with surgical disconnections of the median eminence. These researchers’ contention that VIP promotes the direct release of PRL from pituitary cells was confirmed by in vitro studies (580). Vasoactive intestinal peptide and peptide histidine isoleucine (PHI), which also stimulates PRL release (326, 336, 347, 731), are analogous peptides that are cosynthesized as part of a VIP prohormone (299). By studying the interactions of VIP and PHI in short incubations and superfusion studies, Inoue et al. (294) concluded that both peptides act through a common binding site to enhance PRL release. The VIP (and PHI)-containing fibers arise from the paraventricular nucleus (277), lesions of which block PRL release in reaction to stress (501). Serotonin and also prostaglandin Dz stimulate the release of VIP into portal stalk blood (642, 643), whereas anti-VIP antisera attenuate stress-induced PRL release (1, 325, 328, 551). Martinez de la Escalera et al. (471) showed that the transient removal of dopamine from the medium perifusing rat


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pituitary cells potentiated the ability of TRH, but not VIP, to release PRL. The transient removal of dopamine also potentiated PRL release induced by a calcium ionophore, A23187, or a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), which stimulates protein kinase C (PKC) activity. In contrast, neither CAMP nor forskolin proved to be more effective under these conditions. Martinez de la Escalera and Weiner (474) subsequently reported that in the continuous presence of dopamine, 8-bromoadenosine 3’,5’-cyclic monophosphate (8-BrcAMP) or VIP, but not TRH, increased the magnitude of PRL release in response to a subsequent exposure to TRH. They suggest that VIP may act as a modulator with respect to the action of other PRL-regulating factors. In a series of in vivo studies, Haisenleder et al. (256-259) showed that dopamine antagonists did not enhance the effectiveness of VIP, in contrast to that of TRH, to increase circulating PRL levels. They also suggest that VIP may act in concert with a brief decrease in dopaminergic tone to sensitize the lactotroph to dopamine. Inoue et al. (294) showed that an intracerebroventricular injection of galanin increased the cerebrospinal fluid VIP concentration and plasma PRL level. Although in vitro studies showed that galanin increased VIP release from superfused hypothalamic fragments, galanin did not stimulate PRL release. Treatment of rats with estradiol was shown to increase the VIP concentration in the pituitary but not in the median eminence (585). Earlier studies established that hyperprolactinemia produced by pituitary isografts, transplanted prolactin-secreting tumors, or dopamine antagonists caused a significant decrease in pituitary VIP concentration (538). Conversely, the pituitary VIP concentration was considerably increased in aged rats bearing PRL-secreting pituitary tumors and was postulated to be causally related. These data strongly support the concept that VIP and TRH are physiologically active PRL release-stimulatory agents. The classic concept of a hYP0thalamic peptide that is released into the portal system reaching the lactotroph and stimulating PRL release has to be amended with regard to VIP, because VIP is also synthesized and released by the pituitary lactotroph. Instead, there may be an autocrine-regulated stimulation of PRL secretion by VIP in addition to the “longer loop” effect of the peptide (for further details see sect. III). Apart from TRH and VIP, and serotonin’s action as a potent PRL s timulator via neurotransmission at the hypoth alam ic level, a variety of other substances have been implicated as PRL release-stimulatory compounds. These include oxytocin, substance P, NT, ANG II, the opiates, the Met-enkephalins, and several growth factors (for References see sect. III). Nagy et al. (526) recently showed that the 39-amino ac id glycopeptide comprising the carboxy-terminus of th e neurohypophysial vasopressin -neurophysin precursor stimulates PRL release from cultured pituitary cells as potently as TRH but has no effect on the secretion of

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FIG. 1. Components

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that

regulate

prolactin

release

through

do-

pamine.

other pituitary hormones. Presently it is unknown what contribution these different substances may have in the stimulatory control of PRL secretion. Their possible mechanisms of action are discussed in section III. In Figure 1, a schematic representation of the components that regulate PRL release through dopamine is shown. The responsiveness of the lactotroph to PRL-stimulatory (and inhibitory) compounds by estrogens is discussed in the next section, and recent observations by Ben-Jonathan and co-workers (286, 516, 517) on the presence of a PRL release-stimulatory factor in the normal posterior pituitary gland is discussed in section Iv. VI.

ACTIONS

OF PERIPHERAL

HORMONES

A. Estrogens

The importance of the endogenous estrogen levels in the physiological control of PRL secretion has been reviewed in detail both for rodents (533, 534) and for humans (202). In rats, the proestrous surge of PRL appears estrogen dependent, and circulating PRL levels around puberty and during pregnancy are considerably influenced by the circulating 17-estradiol concentrations in the serum (533). In humans, the differences in basal serum PRL concentrations between men and women and the enormous increase in circulating PRL levels during pregnancy are also largely influenced by estrogens (202). In the rat there are at least three mechanisms by which estrogens stimulate PRL secretion (202). 1) The first mechanism is a direct effect at the pituitary level. Estrogens have been shown to stimulate PRL synthesis, storage, and secretion (25, 330, 346, 445, 480, 544, 716). Estrogens act on the lactotroph by binding to specific cytoplasmic and nuclear binding sites. The subsequent trancription of the PRL gene results in increased synthesis of PRL, whereas the increase in PRL release probably reflects a spillover of hormone from the cells. Apart from the effects on PRL synthesis (419,420), estrogen exerts direc t mitotic effects on lac totroph s, a phenomenon with i mportant con sequen ces to the


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pathogenesis of PRL-secreting tumors in the rat and possibly in humans (11,215,228,300; see sect. IX). 2) The second mechanism is modulation of hypothalamic PRL-inhibitory and -stimulatory factors. Short-term exposure to estrogens for 3-5 days increases the turnover and synthesis of dopamine in the tuberoinfundibular system as well as the dopamine concentration in hypophyseal stalk plasma (141, 170, 248, 571). During long-term estrogen exposure, however, there is a clear reduction in dopamine release into the hypothalamic portal vessels (42, 106). These effects are probably mediated by a direct action of estradiol on the hypothalamus, where it overcomes the facilitatory effect of PRL on dopamine synthesis (19). It is interesting to note that estradiol causes the rapid conversion of a high- to a low-striatal D2 dopamine receptor state; this opens the possibility that it may occur in the pituitary (412). This discrepancy between the effects of short- and long-term estrogen exposure on the hypothalamic release of dopamine is complicated by the possibility that the release of hypothalamic PRL release-stimulatory factors is also induced (528). Jarry et al. (304) reported that the effects of estradiol on the turnover rates of hypothalamic dopamine and GABA was dependent on the presence of pituitary hormones and could not be demonstrated in hypophysectomized rats. The administration of estradiol to rats caused an increase in pituitary TRH receptors, whereas chronic PRL injection produced a decrease in these receptors (639). 3) The third mechanism is an alteration in the pituitary responsiveness to PRL-regulating factors. Estradiol, administered in vitro or in vivo, largely impairs the responsiveness of the lactotroph to dopamine in rats (451, 596, 732), whereas it increases the response of PRL to TRH both in rats and in humans (91, 136, 153, 225, 586, 611). The mechanisms involved include a decrease in the number of dopamine receptors (596) and an increase in the number of TRH receptors on estrogen-treated lactotrophs (135). In conclusion, estrogens exert a stimulatory effect on PRL synthesis by several mechanisms acting at different levels in the hypothalamopituitary unit that regulates PRL secretion. In addition, differences between acute and chronic effects of estrogens are likely, which may explain some of the conflicting effects reported in the literature. The pituitary lactotroph itself may be a fourth level through which estrogens exert their stimulatory activities, as highlighted by the finding that galanin may be an autocrine intracellular mediator of estrogen action on PRL synthesis (see sect. III). In vivo and in vitro experiments in monkeys and in humans indicate that there is an important species difference with regard to the mechanisms used by estrogens to stimulate PRL release. In monkeys, estradiol has little stimulatory effect on PRL secretion in vivo (500), whereas pretreatment of stalk-transected monkeys with estrogen makes the slightly increased PRL release more sensitive to dopamine (536). Similar observations have been reported in humans: dopamine infusion during the follicular phase of the menstrual cycle

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depresses plasma PRL levels more than similar infusions do in hypogonadal women (323). Pretreatment of agonadal women with estrogens elevates basal PRL levels and apparently makes PRL secretion more sensitive to dopaminergic inhibition (324). In vitro studies with cultured monkey and normal human anterior pituitary cells indeed showed that estrogens exert a stimulatory effect on PRL synthesis, but in contrast to what was previously observed in rat pituitary cells, estrogen-exposed primate pituitary cells are significantly more sensitive to the inhibitory effect of dopamine on PRL release (50, 51, 396). The physiological significance of this difference between primates and rodents is presently unknown, but it could suggest new concepts about the pathogenesis of PRL-secreting tumors (see sect. Ix). B. Catecholestrogens

and Exogenous

Antiestrogens

The discovery that the brains and pituitary glands of rats (194,195) and humans (566) possess the enzyme necessary for the conversion of estrogens into Z-hydroxyestrogens suggests a possible role for these metabolites in the regulation of PRL release. The catecholestrogens, 2-hydroxyestrone and Z-hydroxyestradiol, are naturally occurring derivatives of 17-estradiol in humans and in rats, with circulatory concentrations comparable to those of estrone and estriol (194, 566). Both 2-hydroxyestrone and 2-hydroxyestradiol inhibit PRL release by cultured normal rat pituitary cells in a manner that does not involve dopamine receptors or calcium transport over the cell membrane (397). These effects can be clearly demonstrated only if pituitary cells are cultured in the absence of estrogens, whereas both catecholestrogens seem to exert mixed PRL inhibitory-stimulatory actions, depending on the concentrations of compounds added to the incubation medium (32, 397, 422, 582). In vivo administration of catecholestrogens to hypogonadal women results in stimulated PRL release (2); in the presence of estrogens, there is an inhibitory effect on PRL levels (34,196,629). Long-term administration of 2-hydroxyestradiol and Z-hydroxyestrone inhibited both the growth of and hormone secretion by a transplantable rat pituitary tumor (388). In contrast, short-term infusion of 2-hydroxyestradiol alone did not affect hyperprolactinemia in patients with prolactinomas (389). These observations indicate that the action of estradiol on lactotrophs may also be modulated by its metabolites, which have opposite effects on PRL release. 2-Hydroxyestrone exerts a strong anti-estrogenic action on PRL synthesis, whereas Z-hydroxyestradiol seems to have an estrogenic or antiestrogenic effect, depending on the estrogen status. Studies on the effects of exogenous antiestrogens, such as tamoxifen and its metabolites, were initially confusing. In vivo administration of tamoxifen to rats bearing transplantable PRL-secreting pituitary tumors readily inhibited tumor growth and hormone secretion (393, 527, 587), but the actions of tamoxifen on normal


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PRL synthesis and release were less clear. Lieberman and co-workers (417, 418) showed that tamoxifen and 4-hydroxytamoxifen inhibited basal and estradiol-stimulated PRL synthesis by cultured female rat pituitary cells. A biphasic stimulation of PRL release was observed in male rat pituitary cells cultured in a medium that contained a low concentration of estrogens (10, 470), whereas tamoxifen and its metabolites directly inhibited PRL release and reduced the cell number of cultured rat PRL tumor cells when cultured in the absence of estrogen (395). The paramount importance of even extremely low estrogen concentrations or substances that exert estrogen-like activities was shown in studies in which it was demonstrated that phenol red, a pH indicator that is normally present in culture media, exerts estrogen-like activity that obscures, at least in part, the agonist-antagonist activities of exogenous antiestrogens, such as tamoxifen (48,274,283). Direct antiestrogenic action at the hypothalamus, resulting in stimulation of dopamine turnover, may also contribute to the inhibitory effects of these compounds on PRL secretion after in vivo administration (698). C. Other Steroid Hormones

Both long- and short-term administrations of pharmacological concentrations of testosterone stimulate PRL synthesis in castrated male rats (445,743), but these effects may be indirect via conversion of testosterone into estrogens. Glucocorticoids decrease PRL synthesis in GH3 cells (118, 569). These effects are probably exerted via inhibition of PRL gene transcription (182). It is unclear whether glucocorticoids also affect PRL release by the normal pituitary gland (716). Progesterone had no direct effects on PRL synthesis and release by primary cultures of rat (420), ovine (716), and monkey (51) pituitary cells. However, progesterone inhibits estrogen-induced PRL synthesis and release in rat but not in monkey pituitary cells (52,96). In vivo studies on the effects of progesterone and progestins have shown an increase (71, 623) or decrease in PRL secretion (96, 599), whereas no effect of progestin administration on basal and TRH-stimulated PRL release has been observed in normal women (659). Progestins, such as megestrol acetate, and antiprogestins, such as RU 38486, exert a powerful inhibitory effect on tumor growth and PRL release by transplantable rat pituitary tumors in vivo and in vitro (379, 391, 394). The active metabolite of vitamin D, 1,25-dihydroxyvitamin Ds, inhibits basal but potentiates TRHstimulated PRL synthesis in GH4 cells (523). Similar stimulatory effects have been observed by others (265, 715, 726). This vitamin D metabolite probably selectively enhances PRL gene expression in GH4 cells (727), while it markedly enhances the responsiveness of GH4 cells to different secretagogues (725).

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L-Triiodothyronine (T3) inhibits PRL synthesis in cultured normal rat pituitary cells via a decrease in PRL gene expression (479). Hypothyroidism increases PRL mRNA accumulation and PRL release (739). VII.

INTRACELLULAR PROLACTIN

A. Pituitary

MECHANISMS

THAT

REGULATE

RELEASE

Cell Systems

Several PRL-secreting pituitary tumors and pituitary cell lines have been used in attempts to identify the intracellular mechanisms that regulate PRL release. Each of these model systems has distinct strengths and weaknesses. Unlike the MtTWl5 and 7315a tumors (38, 314, 706), the GH cell line, developed by Hinkle and Tashjian (270), increases PRL release after exposure to TRH. Most human PRL-secreting adenomas are responsive to the inhibitory effects of dopamine or its agonists [for review see Thorner et al. (691)]; however, all of the rat transformed pituitary cell lines (GH3, GH4, MtTW15, and 7315a) that release PRL are resistant to dopamine (109, 121, 188, 385), although the underlying causes for this resistance are different. The GH cell lines are devoid of high-affinity dopamine receptors (log), whereas MtTWl5 and 7315a tumor cells exhibit dopamine receptors that are indistinguishable from normal pituitary tissue (109, 110, 113). It is believed that the reasons for dopamine’s ineffectiveness in inhibiting PRL release by MtTW15 and 7315a tumors lie in these cells possessing functional lesions lateral or distal to the dopamine receptor. In related studies, Bouvier et al. (65) and Collu et al. (101) showed that MtTW15 and 7315a tumor cells have subnormal amounts of the G protein a,-subunit; this supports the theory that a structural anomaly in the Dz-receptorial complex may be responsible for the cells’ resistance to dopamine. In a successful attempt to increase the utility of a clonal rat pituitary tumor cell line, GH& Day and Hinkle (121) fused these cells with the normal anterior pituitary cells of lactating rats, resulting in a hybrid cell population, the PRL release of which could be inhibited by low concentrations of bromocriptine. Unfortunately, after several months, the hybrid cell line lost its responsiveness, thus precluding studies on its intracellular components, including its G proteins. Although dopamine does not decrease basal PRL release from 7315a tumor cells, the monoamine decreases stimulated PRL release from the tumor (317). A clonal cell line, designated MMQ, was derived from the 7315a tumor (320); it expresses functional dopamine receptors that are coupled to the inhibitory mechanism associated with PRL release and thus should be of significant aid in studying the mechanisms governing PRL release.


292 B. Adenylate

S. W. J. LAMBERTS

Cyclase and Cyclic Nucleotides

On an operational level, there is good agreement that guanine nucleotide-binding proteins (G proteins) are involved in the transduction of signals across cell membranes [for review see Spiegel (669)]. The stimulatory (G,) and the inhibitory (Gi) proteins are associated with adenylate cyclase in the anterior pituitary gland. Although the function of the G, protein is not firmly established, it is thought to be functionally coupled to the D2 receptor in this tissue (636). It is generally believed that dopamine exerts inhibitory action on PRL secretion by activating a guanine nucleotide-sensitive, high-affinity D2 receptor that can be inactivated by pertussis toxin (111, 221). Several laboratories have demonstrated that this pituitary receptor complex is negatively coupled to adenylate cyclase (122, 177, 229, 303, 320, 553). It is recognized that the resulting dopaminergicinduced decrease in CAMP content may be a contributing factor in the reduction of PRL release, but this is considered secondary in importance to dopamine’s effect on Cazf (626,692). Although CAMP or its analogues can stimulate the release of PRL (132, 260, 684), addition of dopamine abolishes PRL release despite the continued presence of elevated CAMP levels in the cells (130, 134). In contrast to these studies, the catecholamine was found to decrease CAMP concentrations in enriched lactotroph populations (35, 682). On the basis of all available information to d ate, alte ration of lactotroph CAMP levels by dopamin e appears to be a secondary event that is not primarily associated with the early inhibitory events that limit PRL release. Most neuropeptides that enhance PRL release exert no stimulatory action on pi tuitary CAMP levels. An exception to this i.s VIP, which was shown to stimulate pituitary adenylate cyclase activity, CAMP content, and PRL release (313,353,552). The stimulatory effects that VIP and a CAMP analogue have on hormone release are attenuated by nifedipine, an agent that inactivates the voltage-dependent Ca2+ channels (7,8). Earlier, Onali et al. (553) showed that dopamine produces a similar reduction in VIP-induced CAMP production, an effect that may also be related to changes in Ca2+ influx. The transient removal of dopamine from the medium of pituitary perifusion experiments potentiates the release of PRL stimulated by TRH, by the Ca2+ ionophore A23187, or by TPA, a phorbol ester that activates PKC (471). In contrast, the transient removal of dopamine does not potentiate PRL release stimulated by VIP, forskolin, or 8-BrcAMP. These data suggest that cessation of dopamine’s effect on Ca2+ influx can act synergistically with PKC or Ca2+ mobilization to promote PRL release. The enhancement of TRH-mediated PRL release, produced by the transient withdrawal of dopamine, was shown to be mimicked by VIP and 8-BrcAMP by Martinez de la Escalera and Weiner (474). This finding correlates well with their finding that withdrawal of the catecholamine also permits an increase in adenylate cyclase activity (473).

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C. Phosphoinositide

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Metabolism

In addition to the prominent role the adenylate cyclase-CAMP system plays in the mechanism of VIP action, it is now widely accepted that enhanced activity of the phosphoinositide cycle mediates the effects of many other neuroendocrine substances that regulate PRL release. In Figure 2 a schematic diagram of the intracellular mechanisms that regulate PRL release is shown. This classic pathway of signal transduction entails the phosphoinositide-specific phospholipase C (phosphoinositidase)-mediated hydrolysis of the minor lipid phosphatidylinositol 4,5-biphosphate (PIP2), which produces inositol 1,4,5=trisphosphate (IP3) and diacylglycerol. Both of the coproducts generated from this reaction subserve unique intracellular messenger functions [for reviews see Hokin (278), Hokin and Hokin (279), and Berridge (47)]. For example, IP3 promotes the discharge of Ca2+ from bound stores in the endoplasmic reticulum (224). The effectiveness of IP3 appears to be mediated by a specific IP,-binding protein located on the endoplasmic reticulum (250, 251, 668). In addition, GTP also increases Ca2+ release from the endoplasmic reticulum, and it may be that the effects of GTP and IPs on Ca2+ mobilization are related (250,344,668). Also, IP3 may increase Ca2+ uptake into lactotrophs, as it does in other tissues (373,496). The function, if any, that inosito1 phosphates other than IP3 perform in the release of PRL has not been established. sn-1,2-Diacylglycerol interacts with and activates the Ca2+-dependent, phospholipid-sensitive PKC. Several lines of evidence indicate that this enzyme may be involved in PRL release. Protein kinase C is located in normal anterior pituitary (705) and GH3 (163) and GH4 (189) cells. Exposure of GH3 or GH4CI cells to PKC activators (31, 131, 162, 189, 236, 301, 302) or TRH (161, 164,189,301) and also exposure of human pituitary adenomas to TRH (297) result in a redistribution of the enzyme from the cytosol to the cell membranes, and both PKC activators and TRH increase the phosphorylation of similar groups of cellular proteins (162). In addition, PKC activators increase PRL release from anterior pituitary (217, 357, 532, 550, 595, 681) and GH3 (358, 466, 467, 556) and MMQ (320) cells. Finally, TRH increases the intracellular concentration of diacylglycerol in GH3 and GH4C1 cells (465, 597). Despite these findings, it has been recently proposed that PKC may not have as large a function in PRL release as was previously thought (313). An involvement of phosphoinositide metabolism in the stimulation of PRL release was initially sought in studies designed to monitor radiophosphate labeling of membranal phospholipid species in response to different stimulants. Early efforts to characterize short-term modifications of the radiolabeling of inositol lipids demonstrated significant, secretagogue-induced increases in the rate of [32P]orthophosphate incorporation into phosphatidylinositol (PI), phosphatidylinositol 4phosphate (PI-4P), and PIP2 in normal anterior pitu-


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itary cells [for review see Canonico and MacLeod (81)] and in GH3 cells (222). Although several receptor systems that govern PRL release mediate these signals through the phosphoinositide cycle, the TRH receptor has received the greatest attention. Thyrotropin-releasing hormone has been shown to promote [3H]IP, production in normal anterior pituitary cell cultures (29, 68,83,306,321,411) and in cultures of GH3 (160,222,223,456,465,597) and 7315a cells (321), all of which had been prelabeled with [3H]inositol. Similar to its VIP counterpart, the TRH receptor is associated with a GTP-binding protein (24, 269, 438, 468, 679, 738), but this particular protein increases the activity of phospholipase C in an indeterminate manner, while having little effect on adenylate cyclase activity. Furthermore, this TRH-associated GTP-binding protein appears to be distinct from the G, or Gi GTP-binding proteins associated with VIP and dopamine receptors (24,269,468,738). Similar responses have been demonstrated in both normal pituitary and 7315a cell cultures exposed to ANG II (59, 77, 82, 83, 176, 179, 252, 306, 310, 312, 321, 426) or to NT (85,86,306,321). Moreover, the amphibian homologue to mammalian gastrin-releasing peptide, bombesin, stimulates [3H]IP, in both GH3 (465) and GH4CI cells (56, 306). In contrast, VIP has no effect on

Dopamine

AT LACTROTROPH

this pathway. Finally, it is interesting to note that, although activation of muscarinic cholinergic receptors appears to inhibit PRL release in normal lactotrophs (609), the muscarinic agonist carbamylcholine chloride (carbachol) was recently shown to increase [3H]IP, production in the MMQ subclone of the 7315a PRL-secreting tumor cell line (320). Although carbachol appears to promote comparable increases in [3H]IP, levels in the normal anterior pituitary, which apparently are related to GH release (79), the specific cell population that exhibits these responses is unknown. In contrast, the potent PRL-releasing peptides contained in the bovine thymic homogenate thymosin fraction 5 do not augment IP, levels in the rat pituitary, nor do they appear to modify CAMP or guanosine 3’,5’-cyclic monophosphate (cGMP) formation (667). The effect of dopamine on the phosphoinositide cycle has also been investigated. Very early studies showed that dopamine inhibits basal as well as TRHstimulated radiophosphate incorporation into the total phosphoinositide fraction of anterior pituitary fragments; similar responses were also obtained with acute administration of bromocriptine (75, 78,84,87-89,448, 454). It was concluded from these studies that the D2 receptor attenuates some aspect of phosphoinositide metabolism, but it was not possible to ascertain

Ca*+

H,

293

LEVEL

Dopamine

SRIF

HO

PHOSpHoupASE

SRIF

Dopamine

A, I

YCLlCAMPi,

INOSITOL

BISPHOSPHATE

1PROTEIN

KINASE

A 1

I protein

phosphorylation

I

T hormone

release

FIG. 2. Intracellular mechanisms that regulate prolactin release. Releasing hormones with H1 sites of action are angiotensin II, thyrotropin-releasing hormone, neurotensin, and bombesin. Releasing hormones with H2 sites of action are vasoactive intestinal peptide and peptide histidine isoleucine. Releasing hormones with no established site of action are posterior pituitary factor, histamine, acetylcholine, substance P, and oxytocin. DAG, diacylglycerol; PkC, protein kinase C; PS, phosphatidylserine; SRIF, somatostatin.


294

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whether such responses reflect changes in catabolic or biosynthetic processes. Several laboratories have addressed this issue in order to determine whether dopamine inhibits phospholipase C action and therefore IP, production (337, 575). Adenosine has been shown to inhibit hormone release by GH4 cells (156); however, although activation of the A1 adenosine receptor appears directly to inhibit TRH-related [3H]IP, production in these cells (129), there has been relatively poor concensus regarding a similar capability on the part of the pituitary D2 dopamine receptor. Some studies describe partial dopaminergic inhibitions of the [3H]IP, responses elicited by TRH (59, 312, 654) or by ANG II (179,312), whereas others describe no changes in basal IP, levels (472, 473) or those levels elicited by TRH (68, 82, 306), ANG II, NT, or bombesin (83, 306). In this regard, it may be significant to note that a comparable inability of somatostatin (SRIF) to reduce IP, production by these neuropeptides has also been reported. Similary, carbachol- and bradykinin-related IP, responses are unaffected by dopamine in the interspecific (i.e., neuroblastoma X Chinese hamster brain explant) NCB-20 cell line (114). Another report states that, although dopamine has no inhibitory effect on basal [3H]IP, levels, the transient interruption of a prolonged dopamine tonus appears to be paralleled by an increase in [3H]IP, production in the pituitary (472, 473); this latter process may underlie the ability of a transient withdrawal of dopamine (in chronically dopamine-suppressed cells) to potentiate TRH- but not VIP-stimulated PRL release in estradiol-treated rat pituitary cells (474). However, transient withdrawal of dopamine has no effect on TRH-mediated IP, production (473). Finally, another study showed an inability of dopamine to reduce [3H]IP, production during short stimulation by TRH, although a partial reduction in the response was evident over longer periods of stimulation (708). Because these inhibitions are prevented by application of ionomycin, but not 8-BrcAMP, it was suggested that dopamine may reduce IP, generation only as a late effect. However, in isolated pituitary membranes, the enhancement of IP3 production caused by TRH could not be attenuated by dopamine, thus indicating that a cytosolic-dependent event, most likely related to Ca2+, precedes dopamine’s action on phosphoinositide metabolism. Vallar et al. (708) conclude that it is unlikely that there is a direct inhibitory coupling of pituitary D2 receptors to phospholipase C. Journot et al. (312) showed that the inhibitory effects of dopamine on PRL release and IP, production are blocked when anterior pituitary cells are preincubated with islet-activating protein, a substance known to bind to 40-kDa GTP-associated proteins in several tissues, including the anterior pituitary. In this regard, chronic D2-receptor activity seems to regulate phosphoinositide metabolism in the anterior pituitary by attenuating the rate at which mature PI is phosphorylated to PIP2. In normal rat anterior pitu-

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itary cell cultures, prolonged treatment with dopamine or bromocriptine dramatically retards the formation of [3H]PI-4P and [3H]PIP2 but not of [“HIP1 (306); neither SRIF nor its long-acting analogue SMS-(ZOl-995) is effective in modifying this process. It has therefore been suggested that chronic exposure of lactotrophs to dopamine, which results in the normally suppressed release of PRL, is caused by the attenuated phosphorylation of PI to PI-4P’ (by inhibition of PI phosphoryltransferase) and of PI-4P to PIP2 (by inhibition of PI-4P phosphoryltransferase). An effector mechanism responsible for this phenomenon has not yet been identified; however, it may be related to changes in cytosolic Ca2+ activity. In contrast to dopamine exposure, PKC activation does decrease stimulated IP, levels in normal anterior pituitary cells (315) and in GH3 cells (159, 664), and these effects were reversed by a PKC inhibitor. Furthermore, this decrease in stimulated IP, levels is thought to be mediated, at least in part, by decreased phospholipase C activity. D. Arachidonate

In addition to increasing the hydrolysis of PIP2 to IP3 and diacylglycerol, TRH, ANG II, and NT enhance the liberation of arachidonate from the cellular lipids of anterior pituitary cells (76, 316, 321, 447, 606). Furthermore, the dynamics of arachidonate liberation and that of secretagogue-induced release of PRL are similar. Despite this similarity, it is noteworthy that, although TRH, ANG II, and NT each stimulate [3H]PIP2 hydrolysis, the dynamics of the PRL release and that of the arachidonate liberation produced by any one of these secretagogues are substantially different from those produced by the others (606). Dopamine and SRIF attenuate the secretagogue-induced release of PRL and the liberation of arachidonate (316, 606). In contrast to its effects on normal anterior pituitary cells, several groups report that TRH does not increase arachidonate liberation or the production of arachidonate metabolites in GH3 cells (165, 166, 363,465, 597). However, one group reports that TRH augments the production of arachidonate metabolites in GH3 cells (588). The mechanism of secretagogue-stimulated arachidonate liberation is still a subject of controversy. Exposure to ANG II increases both arachidonate and stearate liberation from cellular lipids, suggesting that both phospholipase Al and A2 and/or diacylglycerol lipase are involved in arachidonate liberation (321, 322). This is substantiated by the finding that RHC 80267, a diacylglycerol lipase inhibitor, decreases secretagogueinduced PRL release and arachidonate liberation (76, 316). Other data show that phospholipase A2 inhibitors also decrease PRL release and/or arachidonate liberation from normal anterior pituitary, GH3, and 7315a tumor cells (73, 74, 80, 88, 238, 316, 318, 356). In GH3 cells, synthetic diacylglycerols stimulate increased intracellular concentrations of the products resulting


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from phospholipase A2 hydrolysis, i.e., lysophosphatidylcholine and free arachidonate (364). Whatever enzyme system is responsible for arachidonate liberation, it is apparent that Ca2+ plays an integral part in the process. Increasing intracellular Ca2+ concentration ([Ca”‘]i) by exposure to maitotoxin, a potent Ca2’ channel activator, or to the Ca2+ ionophore A23187 increases PRL release and arachidonate liberation from normal anterior pituitary, GH3, or 7315a tumor cells (316, 355, 358). In contrast, decreasing extracellular Ca2+ concentration ([Ca”‘],) attenuates secretagogue-induced arachidonic liberation and PRL release (316, 606). Because the inhibitory effects of dopamine and SRIF on secretagogue-induced arachidonate liberation are similar to that caused by removal of extracellular Ca2’ and because both of these inhibitors of PRL release decrease Ca2+ fluxes (429, 432, 433, 434), it may be that their effects on arachidonate liberation are related to decreased [Ca2+]i. Although secretagogues increase cellular arachidonate content, the role of arachidonate in PRL release remains obscure. Exogenous arachidonate increases PRL release from anterior pituitary (76, 84, 238) and GH3 cells (362) through a mechanism that may involve Ca2’ mobilization (362, 359). Although there are some reports to the contrary (362), it appears that the increase in PRL release due to arachidonate, Ca2+ mobilizing agents, TRH, ANG II, NT, or VIP is attenuated by inhibitors of arachidonate metabolism (73, 74, 76, 84, 102,316,318,321,322,345). Furthermore, select arachidonate metabolites stimulate PRL release, and, according to several studies, some of these metabolites have a more potent effect than arachidonate (322, 345, 356, 589). Arachidonate is metabolized in pituitary tissue by at least three pathways: 1) the cyclooxygenase pathway to the prostaglandins and their related compounds, 2) the lipoxygenase pathways to the leukotrienes and their related compounds, and 3) the epoxygenase pathway to the epoxyeicosatrienoic acids (90, 322, 355, 573, 588). Cyclooxygenase products and inhibitors of their formation have little effect on PRL release (73, 74,76, 84,316, 355, 356). In contrast, lipoxygenase and epoxygenase products and inhibitors of their formation affect PRL release markedly (316, 318, 321, 322, 345, 356, 589). Therefore lipoxygenase and epoxygenase arachidonate metabolites may be the substances involved in arachidonate-induced increases in PRL release, and these metabolites may play a role in the release of PRL that is stimulated by hypothalamic releasing factors as well. E. Role of Calcium

The evidence that Ca2+ has an important role in PRL release is impressive (674). Pharmacological agents that increase [Ca2+]i, including Ca2+ ionophores (130,624,692), elevated K+ levels (627,685,686), and the Ca2+ channel activators maitotoxin (317, 355, 430, 626, 628) and BAY K 8644 (108, 180, 376), increase PRL release from anterior pituitary and clonal GH, 7315a, and

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MMQ cells. In contrast, in normal anterior pituitary cells, decreasing [Ca”‘], or exposing the cells to Ca2+ channel blockers decreases PRL release in a manner very similar to that caused by exposure to dopamine (317, 431, 692). These treatments, however, have no effect on basal PRL release from GH3 cells (431,511,558). The effects of Ca2+ on PRL release appear to be mediated by calmodulin, because calmodulin inhibitors decrease ‘basal and stimulated PRL release (624, 627) and because the insertion of liposomes containing Ca2+activated calmodulin into pituitary cells increases PRL release (625). Many perifusion studies using dispersed cultured anterior pituitary cells (131, 149, 184, 320, 447, 475, 606, 633) or clonal GH cell lines (5-8, 133, 227, 360,466,467) reveal that TRH, ANG II, and NT produce biphasic releases of PRL, although differences in their dynamic responses exist. The initial response of the lactotroph to TRH and ANG II is a rapid-onset, high-amplitude release of PRL, which is transient despite the continued presence of secretagogue. This response is followed by a sustained, low rate of hormone release (606). In GH pituitary cells, the depletion of intracellular stores of Ca2+ by treatment with small amounts of A23187 (8), by addition of arachidonate (359), or, in normal cells, by the use of Ca2+-free medium (606) greatly attenuates the secretagogue-induced spike of PRL release. The results of several studies now permit the equation of the dynamic patterns of PRL release with similar changes in cytosolic Ca2+ concentrations or fluxes. Exposure of normal anterior pituitary cells (12, 458) or GHs cells (226, 593, 661) to TRH promotes the appearance of biphasic intracellular Ca2+ transients, which precedes PRL release. It is thought that the initial transient peak of [Ca2+]i represents the liberation of bound Ca2+ from its nonmitochondrial stores, catalyzed by IPs generated from the hydrolysis of PIP2, whereas the secondary plateau phase is associated with the increased influx of extracellular Ca2+ through voltage-gated Ca2+ channels (685, 686). Only the plateau phase is sensitive to Ca2+ channel blockers or chelators (8). Angiotensin II produces similar changes in [Ca2+]i as well (12). Enyear et al. (180) demonstrated that BAY K 8644 produced an acute stimulatory effect on PRL release by GH4CI cells, which was largely completed by 30 min. During a period lasting from 30 min to ~18 h, these cells released no more PRL than control cells. Thereafter the cells chronically exposed to BAY K 8644 again exhibited a greater release of PRL for up to 72 h. No concomitant chronic stimulation of GH release was observed. Enyear et al. (180) suggest that the transient depletion of intracellular PRL, caused by a Ca2+ channel stimulator, is not adequate to increase PRL synthesis but rather requires a process of prolonged stimulation (see also Ref. 733). In contrast to the delayed effects that Ca2+ channel activators exert on PRL production, the effect of TRH, an enhancement in the rate of PRL gene transcription, occurs within minutes and then subsides (518). This rapid stimulation may be caused by


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the intracellular redistribution of the Ca2+ phospholipid-dependent PKC (223). The function of dopamine as the principle regulator of PRL release has evoked a diverse spectrum of studies designed to define the mechanism(s) through which this bioamine exerts its inhibitory effect on the lactotroph. Although several metabolic processes may be affected by dopamine, for many years no single system was identified as being dominant over the others. However, the role of Ca2+ in the dopaminergic-mediated inhibition of PRL release is emerging as the primary role, with influence over all other intracellular systems with roles in the hormonal secretory process. Progress in this area of research has been difficult to achieve; the use of mixed anterior pituitary cell preparations can yield ambiguous signals, and most PRL-secreting clonal cell lines have no D2 receptors and thus cannot be used. Nevertheless, investigators have succeeded in providing some important observations on this point. The early work of Schofield (630) showed that TRH increases [Ca2+]i in bovine anterior pituitary cells. In contrast, dopamine reduces basal and attenuates the TRH-mediated increase in [Ca”‘]i. Subsequently, Schofield et al. (631) showed that these effects of dopamine can be prevented by preincubating the cells with pertussis toxin, thus indicating the involvement of a GTP-binding protein. Another stimulator of PRL release, NT, was shown to enhance the uptake of 45Ca2+ by rat anterior pituitary cells, an effect that was also blocked by dopamine (490, 491). Schrey et al. (635) tested this apparent dopamineinduced reduction in [Ca2+]i by novel experimentation. They first incubated pituitary cells with dopamine and then, on its withdrawal, they found the uptake of 45Ca2+ into these cells was greater than that into cells never exposed to catecholamine. Their studies support the hypothesis that dopamine decreases Ca2+ influx in lactotrophs. Recent studies by Login and co-workers (430, 434) examined the role dopamine exerts on the movement of 45Ca2+ in preloaded pituitary cells. In initial observations, it was determined that dopamine inhibited the Ca2+ efflux induced by maitotoxin. In subsequent experiments, basal Ca2+ efflux and PRL release were found to be significantly reduced in the presence of 10 nM dopamine. The influx of 45Ca2+ is also inhibited by dopamine; thus the reduced rate of efflux is probably a manifestation of lowered [Ca2+]i. Similar results have been reported by Lafond and Collu (376). In 7315a tumors (433) or clonal MMQ cells (319, 320), dopamine decreases the Ca2+ influx induced by the Ca2+ channel activator maitotoxin. Recently, several attempts have been made to advance the knowledge of Ca2+ dynamics in lactotrophs by using single cell preparations. Winiger et al. (737) reported the presence of two subclasses of lactotrophs with distinct [Ca2+]i responses to TRH and dopamine. Although TRH increases [Ca2+]i in most rat lactotrophs, the magnitude of the peak response is variable, and even though some cells have no plateau or late phase, other lactotrophs demonstrate a large and prolonged

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plateau response. This heterogeneity among lactotrophs is even more pronounced with regard to their responses to dopamine. Some cells demonstrate a decreased, others an increased [Ca2+]i signal in the presence of dopamine. Malgaroli et al. (458), also using single rat lactotrophs, identified two populations of cells. One population had stable [Ca2+]i and was unresponsive to dopamine; a second population of cells exhibited large [Ca2+]i fluctuations, presumably caused by spontaneous action potentials, that disappeared in the presence of dopamine. The addition of TRH induced a [Ca2+]i transient; the initial peak was apparently the result of a redistribution of intracellular stores, and a subsequent plateau was dependent on influx through voltage-gated Ca2+ channels. Preincubation of the cells with dopamine before TRH stimulation attenuated the amplitude of the peak response and abolished the plateau phase. These data support the contention that dopamine causes hyperpolarization of lactotrophs through classic Dz receptors. In agreement with others, Malgaroli et al. (458) concluded that dopamine reduces Ca2+ influx and also inhibits the redistribution of [Ca2+]i. Ingram et al. (293) also found that dopamine hyperpolarizes the plasma membrane and reduces spontaneous action potentials. Somatostatin is also thought to be a major reguiator of Ca2+ metabolism, the effects of which inhibit the release of many proteins from diverse tissues, including PRL by normal pituitary and GH4 cells. The pituitary membrane receptors for SRIF are coupled to a pertussis toxin-sensitive, GTP-binding protein (352, 353, 741). Studies by Dorflinger and Schonbrunn (155) as well as by Epelbaun et al. (181) demonstrated that the SRIFmediated reduction in PRL release occurs by at least two mechanisms: 1) a decrease in adenylate cyclase activity and CAMP levels and 2) another, and probably more important, mechanism that is independent of CAMP levels. Through this CAMP-independent system, SRIF was found to attenuate spontaneous and evoked activity of Ca2+, in a dose-dependent manner, at concentrations that reduce [Ca”‘]i and suppress PRL release (504). Ishibashi and Yamaji (295) also suggested that dopamine and SRIF reduce PRL release by limiting [Ca”‘]i. Pretreatment of the cells with pertussis toxin abolishes the effect of SRIF on cellular excitability. Somatostatin increases K+ conductance to hyperpolarize the cell, thus Ca2+ blocking Ca2+ entry through voltage-dependent channels. An indirect confirmation of this last point was presented by Login and Judd (429), who demonstrated that 45Ca2+ efflux is attenuated by SRIF, with Ca2+ efflux being the cellular response to changes in [Ca”+]i. The data of Koch and co-workers (351, 354) are in excellent agreement with the observations of Mollard et al. (504). These investigators showed that decreasing the [Ca”‘], abolished the SRIF-induced reduction in [Ca”+]i but did not prevent the hyperpolarization response. Thus the SRIF-induced decrease in [Ca2+]i appears to reauire a decrease in Ca2’ influx. Elevating the


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[K’10 blocked both the peptide-induced hyperpolarization and the reduction in [Ca”‘]i. Hyperpolarization of the cells with gramacidin mimicked the effect of SRIF to decrease [Ca2+]i and prevented any further effect of the peptide; in contrast, tetrabutylammonium, a Kf channel blocker, blocked the effects of SRIF on the membrane potential, on [Ca2+]i, and on hormone secretion. Furthermore, nifedipine, a Ca2+ channel blocker that attenuated the ability of SRIF to reduce [Ca2+]i blocked the inhibition of PRL release. These studies indicate that the primary effect of SRIF is an increase in K+ conductance to hyperpolarize the cell that then secondarily decreases Ca2+ influx. This decreased Ca2+ influx through voltage-gated Ca2+ channels subsequently reduces [Ca2+]; and PRL release and is reflected in reduced 45Ca2+ fractional efflux. F. Phosphorylation of Intracellular

Proteins

Several investigators have attempted to identify the intracellular pituitary proteins that are phosphorylated or dephosphorylated during exposure to TRH and/or dopamine. Thyrotropin-releasing hormone increases the phosphorylation of a specific group of proteins in normal anterior pituitary, GH3, and GH4C1 cells (45, 161, 162, 164, 663). Protein kinase C activators increase protein phosphorylation in a pattern similar to that caused by TRH (45, 162, 663). In contrast, VIP increased the phosphorylation of some proteins that are distinct from those phosphorylated by TRH. Dopamine was found to inhibit the TRH-induced protein phosphorylation in normal anterior pituitary cells, thus strengthening the association of this process and PRL release (45). VIII.

MECHANISM

OF ACTION

BIOLOGICAL

EFFECTS

OF PROLACTIN

AND

ITS

Until recently it was firmly believed that the biological effects of PRL on its target tissues are exclusively mediated via interactions with specific high-affinity binding sites (204, 205, 649). Specific receptors have been shown to exist on a great number of organs in different species (for reviews see Refs. 200, 338, 522, 648). Characterization of the PRL receptor showed that it has a molecular weight of ~40,000 and that it is probably not linked by disulfide bonds to itself or to other subunits (253, 332, 333, 338). The primary structure of the rat liver PRL receptor was recently deduced from a single cDNA clone (64). It has a much shorter cytoplasmic region than the GH receptor, but there is considerable localized sequence identity between these two receptors in both the extracellular and cytoplasmic domains. This suggests that these two receptors originate from a common ancestor. Prolactin receptor levels have been shown to be differentially regulated in different tissues. Estrogens (340,578) and pregnancy (339) stimulate rat liver PRL receptor levels, whereas PRL

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itself and GH induce PRL receptor levels via different actions (33). In this regard, some controversy was reported in that both upregulation and downregulation of PRL receptors was observed, depending on the duration of exposure and on the actual PRL concentration used (154,459, 579). The postreceptor actions of PRL within cells carrying specific PRL binding sites remain pivotal. In a recent review, Rillema et al. (602) stated that “PRL has been shown to enter its target cells, although no intracellular effects of PRL have been identified yet.” It therefore seems unlikely that PRL induces changes in cells via direct intracellular actions. A number of studies employing several PRL-responsive model systems suggest that PRL does not stimulate adenylate cyclase activity or intracellular CAMP levels, while it also does not activate the phospholipases or cause changes in phosphoinositide metabolism, elevated [Ca2+]i, or other ionic concentrations. However, PRL does stimulate the expression of milk protein genes by increasing both gene transcription and mRNA half-life (282,476). With regard to the possible direct mitogenic effects of PRL on breast tissue, much doubt remains. In some studies PRL was reported to stimulate directly the growth of normal mammary glands (290) and breast cancer cells (460), but many studies have not found such a direct mitogenic effect of PRL (173, 699). These contradictory data are surprising against the background of firm evidence that PRL is a powerful cocarcinogen in mammary cancer in intact rodent models [see Kleinberg (349)]. Nicoll and co-workers (542, 543) further studied these discrepancies between the in vivo and in vitro actions of PRL on pigeon crop sac cells. In analogy with the observation that most of the biological actions of GH are effected via peripherally synthesized intermediary growth factors (insulin-like growth factors), they proposed the existence of a liver-derived serum factor called “synlactin,” which potentiates and/or mediates at least part of the effects of PRL on the stimulation of crop sac proliferation (498, 542, 543). It has not been determined yet, however, which biological actions of PRL in what organs indeed are effected via synlactin. In human serum the presence of a nonlactogenic factor has been demonstrated that synergistically enhances PRLstimulated growth of Nb2 rat lymphoma cells in vitro (485). Very recently, Frawley et al. (209) showed further evidence for a modification of the synlactin hypothesis. These investigators used a bioassay for lactogenic activity by measuring casein production by individual mammary cells through the use of the reverse hemolytic plaque assay (208). Their results show that PRL itself mainly causes an increase in the number of plaqueforming mammary cells, whereas the incubation medium obtained from the liver of lactating rats mainly increases the individual plaque size and the steadystate levels of PRL on RNA. This “liver lactogenic factor,” which was present in normal rat serum, was stimulated by the infusion of PRL in vivo and was (indirectly) inhibited by bromocriptine administration.


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These studies, which suggest that the biological actions of PRL (as in the case of GH) seem to be at least partially mediated via the generation of a (mainly liver derived?) intermediate growth factor, also force us to reconsider the interpretation of the results of many in vitro and short-term in vivo studies on the biological responses to PRL. Prolactin shows a broad spectrum of biological actions. In contrast to other pituitary hormones, it is not so specific as to regulate one or few functions, but it is involved in a wide variety of physiological processes of diverse organ systems (199,200). Nicoll and co-workers (541,542) categorized these actions from a comparative point of view in six general categories: 1) regulation of water and electrolytic balance, 2) control of growth and/or development, 3) metabolic effects, 4) reproductive actions, 5) effects on integumentary (ectodermal) structures, and 6) interactions with steroid hormones. In rodents and in primates, including humans, the regulatory actions of PRL on lactation (mammary growth and differentiation, initiation of milk secretion, and maintenance of lactation) and on reproduction have been studied extensively (for reviews see Refs. 199,484, 648,650, 704). The current problems inherent in interpreting the mechanism of action of PRL and also the meaning of its biological responses can be demonstrated both in the fields of behavior and immunology. Prolactin stimulates maternal behavior in female rats if the animals have been exposed to the hormone for a considerable period (67). Acute priming with PRL, however, showed that, depending on the length of PRL exposure, differential effects on maternal behavior can be observed (436). Prolactin enhances grooming behavior in rats, but the extent of this effect greatly depends on the duration of hyperprolactinemia in the experimental animals (157). In the field of immunology, it was shown that PRL can stimulate the immune system in a biphasic manner and that a reduction in the basal PRL levels attenuates immune responses (523,524,666) and alters the age-dependent expression of lymphocyte surface antigens (610). Prolactin is involved in the maintenance of T-cell immunocompetence, whereas the immunosuppressive effects of cyclosporine may be mediated by the displacement of PRL from binding sites on lymphocytes (267, 561). IX.

IMPLICATIONS SECRETION

FOR

ABNORMALITIES

OF PROLACTIN

IN HUMANS

Spontaneous hyperprolactinemia is common in aging female rats and is often accompanied by increased pituitary weight, hyperplasia of the lactotroph, and the development of PRL-secreting pituitary tumors (298, 367,483, 703). In the rat, estrogen administration results also in enhanced PRL secretion, lactotroph hyperplasia, and, ultimately, in tumor induction (495,734). Pituitary microadenomas were found at autopsy in 32 of

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120 (27%) pituitaries in people who had no clinical evidence of pituitary disease during life (69). Forty-one percent of these adenomas were indentifial as PRLcontaining tumors. The etiology of prolactinomas in humans is unknown. It was suggested that the apparent increase in the incidence of prolactinomas may have been related to the use of estrogen-containing contraceptives. This assumption was originally based on the observation that estrogens cause hypertrophy of lactotrophs during normal pregnancy (22). Growth of prolactinomas during pregnancy was also observed in some patients (219, 390). As mentioned in section VI, it has been shown that cultured normal human pituitary cells become more sensitive to dopamine during estrogen exposure (396), an observation that contrasts sharply with that seen in the rat, where estradiol attenuates the normal inhibitory control of PRL release by dopamine (596). This observation suggests that estrogens in humans are not an important factor in the pathogenesis of prolactinoma formation. In accordance with this, it was reported that normal healthy women using lowdose estrogen-containing oral contraceptives have no (120) or only slightly elevated (284) circulating PRL levels, whereas epidemiological studies indicate that estrogens play an insignificant role in pituitary tumor formation (574). However, estrogens may cause growth of previously clinically silent prolactinomas, even if they do not cause them. Estrogen treatment of one male-to-female transsexual patient, however, was indeed shown to result in pituitary tumor formation (234). In experimental studies, it was shown that bromocriptine effectively controls hyperprolactinemia and tumor growth both in rats with spontaneous and with most estrogen-induced pituitary tumors (482, 581). In humans, bromocriptine has been shown to be effective in normalizing the elevated PRL levels in 95% of patients with microadenomas, whereas galactorrhea disappeared in virtually all patients, and ovulation, normal menstrual cycles, and fertility were restored in most of these patients (46, 232, 503, 694, 689). Apart from an inhibitory effect of bromocriptine on PRL secretion, it has become clear that chronic treatment with bromocriptine also results in shrinkage of prolactinomas in ~75% of patients. This was shown by a decrease in the size of the tumor at computerized tomography scanning and/or by an improvement in the visual acuity and visual field defects; it is also shown by a partial or complete normalization of the initially disturbed anterior pituitary function (20, 404, 441, 693, 695, 728). In normal and tumorous rat lactotrophs, bromocriptine and other dopamine agonists primarily inhibit PRL secretion (444,453). However, PRL synthesis (444, 453) and PRL mRNA concentrations are also (secondarily?) suppressed (477), while an increased intracellular degradation of newly synthesized PRL within lactotrophs was observed (117, 478). Bromocriptine inhibits the proliferation of estrogen-exposed PRL-secreting rat pituitary tumor cells via inhibition of DNA synthesis (119, 425, 581). The mechanism of the bromocriptine-


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1990

REGULATION

OF PROLACTIN

SECRETION

mediated shrinkage of human prolactinomas has been extensively reviewed (377). In summary, it is presently thought that primarily bromocriptine acts to inhibit PRL secretion, and secondarily the agent also inhibits the synthesis of PRL within the tumor. This eventually results in a decrease in the intracellular PRL stores in the tumor cells and a decrease in the size of the hormone-synthesizing apparatus of the cells. This chain of events results in a decrease in the volume of each individual tumor cells and in shrinkage of the tumor as a whole. No changes in the vascularity of the tumors, necrosis, or cytotoxic effects have been observed in human prolactinomas during or after chronic treatment with bromocriptine (14, 36, 402, 403, 697). These observations are substantiated by the fact that tumor shrinkage appears, in most cases, to be reversible. Withdrawal of bromocriptine therapy after ~1 yr causes the tumor size to increase to what it was before treatment, while increasing PRL levels are also observed in most patients. However, this rather simple mechanism of tumor shrinkage may not be applicable to all patients, since only 12 of 69 patients with prolactinomas (from 3 different series of patients) showed persistent normalization 2.5 yr after withdrawal of chronic bromocriptine therapy (271,469, 512). Some evidence suggests that the process(es) that leads to the bromocriptine-induced suppression of elevated PRL levels and those that control (estrogen-induced) tumor growth may be, at least partially, independent (723,734). This possibility is supported by studies in humans where Molitch et al. (503) showed that in virtually all cases bromocriptine therapy of patients with PRL-secreting macroadenomas suppressed PRL levels, whereas there was no correlation betweeen the extent of tumor size reduction and the percent age fall in circulating PRL concentrations. A possible explanation for this discrepancy might be offered by the suggestion by Weiner’s group that bromocriptine inhibits (estrogen-induced) pituitary tumor growth in rats at least partially by reducing the vascularization of these tumors. These investigators originally showed that exposure of rats to estrogen caused a rapid increase in the arterial blood supply of the hyperplastic pituitary glands (171), whereas bromocriptine therapy dramatically decreased the estrogen-induced arteriogenesis in parallel with a decrease in pituitary weight (172). In favor of a role of abnormal arteriogenesis was the recent observation by Racadot (590) that even at the microadenoma stage human pituitary tumors contain a considerable number of arterial vessels contrasted to the normal pituitary gland. Very long-term bromocriptine therapy has become the primary modality of therapy of patients with prolactinomas. This concensus is substantiated by the high recurrence rate of hyperprolactinemia in patients who initially showed complete remission after transsphenoidal surgery (637). To optimize life-long therapy of prolactinoma patients with dopamine agonists, new compounds are currently under investigation that have

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a longer period of action and that may be better tolerated (193, 203, 350,489, 594). We acknowledge the help and assistance of Anke de Graaff, Dr. Allan M. Judd, W. David Jarvis, and Jo Ann M. Eliason, all of whom greatly contributed to the preparation of this review. REFERENCES 1. ABE,

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Influence of lactotroph cell density on prolactin secretion in rats.

The biphasic regulation of prolactin secretion by dopamine agonist-antagonists.

Corticosteroid regulation of gonadotropin and prolactin secretion in the rat.

The inability of bromocriptine to inhibit prolactin secretion by transplantable rat pituitary tumors: observations on the mechanism and dynamics of the autofeedback regulation of prolactin secretion.

Regulation and adaptation at the molecular level.

A normal ovulatory woman with hyperprolactinemia: presence of anti-prolactin autoantibody and the regulation of prolactin secretion.

Lactation and the physiology of prolactin secretion.

Repeated injections of cocaine inhibit the serotonergic regulation of prolactin and renin secretion in rats.

No involvement of alpha 2-adrenoceptors in the regulation of basal prolactin secretion in healthy men.

Neuropharmacological regulation of episodic growth hormone and prolactin secretion in the rat.

Disorders of prolactin secretion.

Control of prolactin secretion.

Spatial regulation of cytoplasmic snRNP assembly at the cellular level.

Dynamics of epigenetic regulation at the single-cell level.

Regulation of alternative splicing at the single-cell level.

Regulation of oxytocin action at the receptor level.

The physiological role of thyrotropin-releasing hormone in the regulation of thyroid-stimulating hormone and prolactin secretion in the rat.

Antidopaminergic activity of estrogens on prolactin release at the pituitary level in vivo.

Effect of substituted benzamides on prolactin secretion in the rat.

Ibopamine-induced reduction of serum prolactin level and milk secretion in puerperal women.

Evidence for the autoregulation of hormone secretion by prolactin.

Hypothalamic Effects of Tamoxifen on Oestrogen Regulation of Luteinising Hormone and Prolactin Secretion in Female Rats.

Dissociation of dopamine from its receptor as a signal in the pleiotropic hypothalamic regulation of prolactin secretion.

Evidence that the regulation of diphtheria toxin production is directed at the level of transcription.