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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 858-863
Copyright © 2003 by The Endocrine Society

Leukemia Inhibitory Factor Regulates Prolactin Secretion in Prolactinoma and Lactotroph Cells

Anat Ben-Shlomo, Irina Miklovsky, Song-Guang Ren, William H. Yong, Anthony P. Heaney, Michael D. Culler and Shlomo Melmed

Division of Endocrinology and Metabolism (A.B.-S., I.M., S.-G.R., A.P.H., S.M.) and Department of Pathology (W.H.Y.), Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles, California 90048; and Biomeasure Inc. (M.D.C.), Milford, Massachusetts 01757

Address all correspondence and requests for reprints to: Shlomo Melmed, M.D., Academic Affairs, Room 2015, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Leukemia inhibitory factor (LIF) stimulates the hypothalamic-pituitary-adrenal axis, and transgenic mice overexpressing pituitary LIF develop Cushing-like syndrome accompanied by reduced prolactin (PRL) expression. Effects of LIF were, therefore, tested on PRL expression in human prolactinomas and normal and tumorous rat lactotrophs. Normal human pituitary tissue expressed LIF, as well as the LIF receptor (LIFR) signaling subunits, gp130 and LIFR. Although all of 19 prolactinomas tested expressed gp130 and LIFR subunit mRNA and immunoreactive protein, only 3 of 19 prolactinomas expressed LIF mRNA. All of four prolactinomas had no detectable LIF immunoreactivity, in contrast to all other pituitary tumor types that expressed LIF. LIF (5 nM) treatment reduced PRL secretion in primary human prolactinoma cultures by up to 42% (P < 0.0005), an effect that was surprisingly blocked by sulpiride, a D2-like dopamine receptor antagonist. LIF (5 nM) also suppressed PRL levels in primary rat pituitary cultures by 70% (P < 0.005), and in rat MMQ pituitary tumor cells, and this effect was also reversed by sulpiride (200 µM). D2R agonist suppression of PRL was not additive with LIF. GH levels in these cells were unchanged by LIF, consistent with a selective effect on PRL. Transfection of human long-form D2R into an LIF-resistant MMQ cell clone restored LIF responsiveness. These results show that even though human prolactinomas express gp130 and LIFR, and respond to exogenous LIF, albeit less than normal lactotrophs, they are largely devoid of LIF. These observations indicate a role for LIF in loss of autocrine PRL suppression contributing to unrestrained prolactinomas PRL secretion. Moreover, PRL suppression by LIF may be mediated by gp130 and D2R interaction.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LEUKEMIA INHIBITORY FACTOR (LIF), a polyfunctional cytokine mediating hematopoietic and metabolic functions, also acts as a neuroimmune mediator of the hypothalamic-pituitary-adrenal axis (1). LIF is expressed in normal, tumorous, and fetal corticotroph cells and induces proopiomelanocortin gene expression and ACTH secretion, and pituitary-directed transgenic LIF overexpression results in Cushing’s syndrome (2).

LIF belongs to the gp130 cytokine signaling family that comprises IL-6, IL-11, CT-1, OSM, and others (1, 3). LIF binding to the heterodimeric LIF [LIF receptor (LIFR)] and gp130 receptor subunits activates Jak1, Jak2, and tyk2 kinase, followed by phosphorylation of tyrosine residues on the receptor subunits, providing docking sites for the Src homology 2 domains of signal transducer and activator of transcription (STAT) proteins. This enables phosphorylation and homo- or heterodimerization of STAT1, STAT3, or STAT5, which translocate to the nucleus, bind specific DNA STAT-binding elements, and activate transcription (1, 4).

Several lines of evidence have implied that LIF might also effect lactotroph cells. Transgenic mice overexpressing pituitary-directed LIF driven by the rat GH promoter exhibited increased corticotroph cell number and enhanced ACTH secretion, with a 26% reduction in pituitary lactotroph cells, an approximately 70% decrease in prolactin (PRL) mRNA, and an approximately 30% reduction in serum PRL levels (5). Somatotroph number and function were similarly suppressed when transgenic LIF was overexpressed by the pituitary glycoprotein hormone {alpha}-subunit. Similar corticotroph hyperplasia and lactotroph, somatotroph, and gonadotroph hypoplasia developed (2).

Dopamine, the major inhibitor of PRL secretion, accounts for most of the tonic lactotroph inhibition. Additional factors have also been implicated (6, 7). Because overexpressed LIF reduced PRL levels in transgenic mice, we assessed LIF regulation of human prolactinomas and tumorous rat lactotroph cells. We demonstrated that exogenous LIF inhibits human and rat PRL secretion, and although LIF is expressed in functional and nonfunctional pituitary tumors, it is undetectable in most human prolactinomas.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Peptides and plasmids

Recombinant murine LIF was obtained from Chemicon International (Temecula, CA); D2R agonist BIM-53097 with permission from Biomeasure Inc. (Milford, MA); and -(-) Sulpiride and 2-Bromo-{alpha}-Ergocryptine from Sigma (St. Louis, MO). The human long-form D2R cDNA inserted into pcDNA3.1/GS vector was obtained from Research Genetics, Inc. (Huntsville, AL).

Cell cultures

Human pituitary adenoma specimens were freshly obtained at the time of transsphenoidal surgery, as approved by the Institutional Review Board. Normal female rat pituitary cells were prepared as previously described (8), modified from Conn and Rogers (9). Pituitary tissue was enzymatically dissociated in DMEM medium containing 0.35% collagenase, 0.15% hyaluronidase, and 0.3% BSA (all from Sigma) at 37 C for 45 min. Cells were then incubated in 96-multiwell tissue culture plates, 4 wells for each treatment group, containing 10% fetal bovine serum (FBS) in DMEM medium for 48 h, and then serum deprived in 0.3% BSA serum-free medium for an additional 3–4 h. Serum-free medium was collected after 20 h and stored at -20 C until hormone assay. Tumorous rat lactotroph MMQ cells (American Type Culture Collection, Manassas, VA) were grown in phenol-free RPMI supplemented with 7.5% horse serum (Omega, Tarzana, CA), 2.5% FBS, and 1% anibiotic-antimycotic (Life Technologies, Inc., Gaithersburg, MD).

GH3 cells were grown in low-glucose DMEM, 15% horse serum, 12.5% FBS (Omega), 2 mM L-glutamine, and 1% anibiotic-antimycotic (Life Technologies, Inc.).

Measurements of mRNA expression by reverse transcriptase (RT), followed by PCR

Normal human anterior pituitary RNA was obtained from Zoion Diagnostics (Shrewsbury, MA). Human pituitary adenomas were harvested and kept at -70 C for RNA extraction. Tissues were homogenized, and total RNA extracted using TRIzol (Life Technologies, Inc.). One microgram of each RNA sample was treated with Dnase I (Ambion, Inc., Austin, TX) to eliminate contaminating genomic DNA. RNA was used in a 20-µl RT reaction containing Oligo(dt) as a primer and PowerScript reverse transcriptase (CLONTECH Laboratories, Inc., Palo Alto, CA). Samples with and without RT as negative controls were incubated at 42 C for 1 h. Reaction volume was diluted five times in diethylpyrocarbonate-treated water. The 5-µl aliquots from the generated cDNA and negative controls were used for subsequent PCR. All RT products were checked for 18S using QuantumRNA 18S Internal Standards (Ambion, Inc.). Human LIF, LIFR, and gp130 receptor subunit screening of human tissue was performed by PCR amplification using Titanium Taq DNA polymerase (CLONTECH Laboratories, Inc.). The primers (Invitrogen, Carlsbad, CA) used were: hLIFR (5'-AAGATATAGCTGCAGAAGAGG-3', 3'-TAACAATACTTCACAGGAT-5'); hLIF (5'-CTGTTGGTTCTGCACTGG A-3', 3'-GGGTTGAGGATCTTCTGGT); hgp130 receptor subunit (5'-CATGCTTTGGGTGGAATGGAC-3', 3'-CATCAACAGGAAGTTGTTCCC-5'). RT-PCR was also performed for rat gp130 receptor subunit in MMQ cells using the primers (5'-GCACGGCTCATATGGAAGAC-3', 3'-GATGGCGGTGTCCATTCTAC-5').

Immunohistochemistry

Ten-micrometer sections were cut from formalin-fixed, paraffin-embedded prolactinomas, ACTH-secreting adenomas, and autopsy-derived normal human anterior pituitary tissue. Sections were stained using antibodies against human PRL (1:1000), human ACTH (1:1000), human gp130 (1:20 dilution, Santa Cruz Biotechnology, Inc., Santa Cruz, CA), human LIFR{alpha} (1:20 dilution, R&D Systems, Minneapolis, MN), and human LIF (1:75 dilution, R&D Systems). Staining was detected by the avidine-biotin-peroxidase method. Negative controls for each tissue included antibody-free samples and adsorbed antiserum.

PRL RIA

Human PRL measurements were performed using a kit (Diagnostic Products Corp., Los Angeles, CA). Rat PRL was assessed using RIA reagents kindly provided by Dr. Parlow from the National Hormone and Peptide Program (Harbor-UCLA Medical Center, Torrance, CA). All samples were appropriately diluted to achieve midrange assay concentrations.

Transient transfections

A clone of MMQ cells resistant to D2R agonists and LIF were plated in 2-ml dishes (150,000 cells per well) in serum-free medium and 0.3% BSA. The gp130 receptor subunit mRNA was detected in these cells by RT-PCR. Cells were transiently cotransfected with 1 µg human long form-D2R or 1 µg human gp130 receptor subunit and 0.5 µg ß-galactosidase (Sigma) using FuGene 6 (Roche, Indianapolis, IN). After a 24-h incubation, serum was collected and ß-galactosidase reporter gene reactivity measured.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
LIF is undetectable in human prolactinomas

All of eight GH- and four ACTH-secreting human pituitary adenomas and three normal human anterior pituitary tissues tested expressed LIF mRNA. In contrast, LIF mRNA was not detectable in 16 of 19 prolactinomas when analyzed by RT-PCR (Table 1Go). LIFR and gp130 were expressed in all prolactinomas, GH- and ACTH-secreting adenomas, and normal human anterior pituitary tissue. Human prolactinomas also did not express LIF immunoreactivity in contrast to normal human anterior pituitary tissue and human ACTH-secreting adenoma, which exhibited LIF immunostaining (Fig. 1Go). Prolactinomas were immunoreactive for gp130, albeit weakly, compared with normal human anterior pituitary tissue and human ACTH-secreting adenoma, which abundantly expressed gp130 (Fig. 1Go).


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  		Table 1. Human LIF, LIFR, and gp130 receptor subunit mRNA expression in human prolactinoma

 


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  		Figure 1. Human pituitary tissue immunoreactivity (magnifications: a, b, and e, x40; c, d, and f–i, x10) to antihuman LIF, gp130, PRL, and ACTH antibodies detected by avidine-biotin-peroxidase. a, d, g, Autopsy-derived consecutive slices of normal human anterior pituitary stained for LIF, gp130, and PRL, respectively. Prolactinoma is devoid of LIF. b, e, h, Human prolactinoma stained for LIF, gp130, and PRL, respectively. c, f, i, Human ACTH-secreting adenoma stained for LIF, gp130, and ACTH, respectively.

 
LIF reduces PRL secretion in human and rat lactotroph cells

Incubation of human prolactinoma cell cultures for 20 h with 5 nM LIF reduced PRL secretion by up to 42% (P < 0.0005) (Fig. 2Go). Addition of a D2R agonist (2 nM) reduced PRL levels by up to 65% (P < 0.0005), but cotreatment with LIF and D2R agonist was not additive for PRL suppression. In similar experiments performed in primary rat pituitary cell cultures, LIF (1 nM and 5 nM) reduced PRL secretion by 42% and 70% (P < 0.0005), respectively, after 20 h of treatment (Fig. 3Go). The D2R agonist reduced PRL by 45% (P < 0.002), and cotreatment of LIF (1 nM or 5 nM) with D2R agonist (2 nM) further reduced PRL levels by 82%, a partially additive effect, especially for the lower dose of LIF (Fig. 3Go). In tumorous rat MMQ lactotroph cells, PRL secretion was attenuated by 25% after 20 h of treatment with 5 nM LIF (P < 0.002) and by 50% with 100 nM LIF (P < 0.0005) (Fig. 4Go). Rat normal lactotroph cells were three times more responsive to 5 nM LIF, compared with tumorous rat lactotrophs.



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  		Figure 2. A and B , Cultured prolactinoma cells. Cultures were incubated for 48 h before 20-h serum-free treatment with LIF, D2R agonist, sulpiride, or combinations. One nanomole of LIF (), 5 nM LIF ({blacksquare}), and D2R agonist (2 nM) suppress human PRL in prolactinoma cells (P < 0.0005, compared with controls in {square}). Cotreatment was not additive. PRL suppression by either LIF or D2R agonist or cotreatment is reversed by sulpiride (200 µM), except from prolactinoma B treated with the higher dose of LIF and D2R agonist (P < 0.005, compared with groups treated with D2R agonist and LIF 1 nM). Each value represents mean ± SEM of four wells.

 


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  		Figure 3. One nanomole of LIF (), 5 nM LIF ({blacksquare}), and D2R agonist (2 nM) and sulpiride regulation of PRL suppression in rat lactotroph cells (P < 0.0005, compared with controls in {square}). Cultures were incubated for 48 h before 20-h serum-free treatment with the indicated treatment. Results represent the mean of three independent experiments and each value represents mean ± SEM of four wells per experiment.

 


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  		Figure 4. Dose dependency for LIF suppression of PRL in MMQ rat lactotroph cells treated for 20 h (*, P < 0.001, compared with untreated group). The curve represents sulpiride cotreatment with the indicated respective LIF doses. Each value represents mean ± SEM of four wells.

 
LIF action is blocked by a D2-like dopamine receptor antagonist

As expected, addition of sulpiride, the D2-like dopamine receptors antagonist, reversed the D2R agonist effect on both prolactinoma and normal lactotroph cells, reverting PRL levels back to control levels or modestly higher than control untreated cells (only in MMQ cells). Surprisingly, sulpiride also reversed LIF-mediated reduction of PRL secretion, although by itself did not appreciably alter PRL levels in human prolactinoma and rat normal lactotroph cells. Sulpiride (200 µM) reversed D2R agonist-inhibiting action in normal rat lactotrophs treated with either 1 nM or 5 nM LIF but did not completely reverse the effects of combined LIF (5 nM) and D2R agonist (2 nM) treatment (Fig. 3Go).

LIF suppression of PRL secretion is restored by D2R expression

When an MMQ cell subclone resistant to D2R agonist and LIF action was transfected with the long-form hD2R, LIF and bromocriptine responsiveness were restored (Fig. 5Go). Vector or hD2R transfectants alone secreted similar PRL levels. LIF suppressed PRL by 64% (P < 0.005) in cells expressing the transfected hD2R but did not alter PRL secretion by vector transfectants. PRL was suppressed by 75% (P < 0.0005) after treatment with the D2R agonist only in cells expressing the hD2R, and the D2R agonist was ineffective in vector transfectants.



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  		Figure 5. Expression of human D2R () or vector ({square}) in a dopamine-resistant MMQ cell clone restores LIF responsiveness (64% PRL reduction vs. LIF treated vector group, P < 0.005) and D2R agonist (75% PRL reduction vs. D2R agonist-treated vector group, P < 0.0005). Cells were transiently transfected either with vector or hD2R-containing vector 24 h before treatment with either LIF (20 nM) or D2R agonist (40 nM) for an additional 24 h. Each value represents mean ± SEM of three wells.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results shown here demonstrate that LIF regulates PRL secretion from normal and tumorous lactotroph cells. Moreover, the evidence for LIF acting in concert with dopamine to regulate PRL suggests interaction between LIF and dopamine lactotroph signal transduction pathways. Human prolactinomas appear devoid of LIF at the level of both gene and protein expression, in contrast to human ACTH-secreting adenoma and adult normal human anterior pituitary, which express LIF, as demonstrated in this study and previously shown by us (8). Even though prolactinomas do not express LIF, they do express LIFR subunits, LIFR, and gp130 and respond to exogenous LIF by down-regulating PRL secretion. This effect was demonstrated in cultured human prolactinoma cells derived from both female and male subjects and tumorous rat lactotroph cells. Human PRL-secreting adenomas were more responsive to LIF, compared with the faster growing transformed MMQ rat lactotroph cells. Tumorous cells were also less responsive to LIF action than normal rat lactotroph cells. Prolactinomas are also less responsive to LIF than to equivalent doses of D2R agonist; moreover, LIF and the D2R agonist were not additive in tumor cells in contrast to their action in normal lactotroph cells. The above evidence suggests that LIF may play a role in prolactinoma pathogenesis because it appears that LIF expression is lost in prolactinomas and its paracrine inhibitory action abrogated, compared with normal lactotrophs. The more proliferative lactotroph cells become, the less responsive they are to LIF. Unrestrained PRL secretion by prolactinomas may, therefore, be exacerbated by loss of LIF autocrine/paracrine secretion and partial resistance to LIF action because of relative down-regulation of gp130 receptor expression.

Normal lactotroph cells exhibited approximately 2-fold greater reduction in PRL levels, compared with tumorous cells when treated with LIF. Cotreatment with the D2R agonist was partially additive for PRL suppression, unlike in prolactinoma cells. In addition, higher concentrations of sulpiride reversed the LIF effect but did not reverse the combined effect of high-dose LIF and the D2R agonist. These results imply that normal lactotroph cells are more responsive to the inhibitory effect of LIF on PRL secretion than tumoral lactotroph cells.

These results may account for low levels of PRL observed in LIF-overexpressing transgenic mice (2, 5). Pituitary LIF overexpression during fetal ontogenesis induces corticotroph cell lineage proliferation and secretion along with inhibition of lactotroph cell development, resulting in high levels of cortisol and low levels of PRL. High glucocorticoid levels during fetal pituitary development also suppress lactotroph cell differentiation (10); therefore, lactotroph cell repression in LIF transgenic mice could also be attributed to higher ambient glucocorticoids levels. However, the PRL inhibitory effect of LIF implies an additional direct effect of the cytokine on the lactotroph lineage.

LIF is required to maintain elevated hypothalamus-pituitary-adrenal axis activity with higher glucocorticoid levels during prolonged stress (11, 12). High LIF levels during chronic stress could contribute to reduced PRL levels, in addition to higher circulating glucocorticoid concentration (6).

Cotreatment with both the dopamine agonist and LIF was not additive in lactotroph cells, raising the possibility that these agents may signal by a common pathway in lactotrophs. Alternatively, the partially additive D2R agonist and LIF inhibition demonstrated in normal rat lactotroph cells might support the existence of another intracellular signaling pathway that may be altered when lactotroph cells become tumorous.

Surprisingly, sulpiride, a D2-like dopamine receptor antagonist known to inhibit D2R agonist action, also reversed LIF-induced reduction of PRL levels. Moreover, transfection of MMQ cells resistant to D2R agonists and LIF with the human D2R restored their capacity to respond to both agents.

These results suggest the existence of an interaction between dopamine receptor signaling and either LIFR or gp130 receptor (intramembranal or soluble) subunits in lactotrophs. This interaction could occur at the level of the receptors themselves or downstream along the intracellular signal transduction pathways. Because IL-6 was shown to have a similar albeit more modest effect on lactotrophs (data not shown), we assumed that the gp130 receptor subunit either directly or indirectly may interact with dopamine signaling. Both LIF and dopamine may, therefore, act through the gp130-LIFR complex and D2R, respectively, but also possibly through a D2R-gp130 functional unit. This proposed interaction might explain some known relationships between PRL and ACTH in the literature. First, bromocriptine treatment increases serum ACTH and cortisol levels (by ~20% and 40–220%, respectively) and reduces serum PRL levels in normal subjects (13, 14, 15, 16, 17), an effect blocked by sulpiride (13). ACTH and cortisol levels were also increased following administration of other dopamine agonists including apomorphine (18) and L-DOPA (19). This phenomenon could occur if the D2R agonist simultaneously activates both D2R and gp130 signaling. ACTH secreting adenomas may manifest during bromocriptine treatment for hyperprolactinemia that eventually turned out to be caused by a prolactinoma (20, 21, 22). This could be explained if bromocriptine also signals through the gp130/D2R functional unit, hence stimulating corticotroph cells and enhancing the appearance of an ACTH-secreting adenoma.

LIF levels are also increased in a variety of inflammatory conditions (12, 23, 24). A 10-fold increase in LIF mRNA accompanied by an approximately 4-fold increase in ACTH and corticosterone levels was observed 4 h after lipopolysaccharide (LPS) injection to normal mice (24). LPS also decreases PRL secretion from rat lactotroph cells (25) and human decidual cells (26). Rat serum corticosterone level increases and PRL decreases 4 h after a burn injury (27). Bromocriptine suppresses the rat inflammatory response induced by LPS (28) and, as mentioned above, increases ACTH and cortisol levels. This implies that both LIF and bromocriptine may stimulate the same or similar pathway. Thus, high LIF levels may bind the LIFR/gp130 receptor complex to increase ACTH and cortisol but may also stimulate a putative gp130/D2R functional unit to reduce PRL levels. In the same manner, bromocriptine binds the D2R to reduce PRL but may also signal to increase ACTH and cortisol levels. Although gp130 and LIFR are ubiquitously expressed in pituitary lactotroph, somatotroph, and corticotroph cells, LIF itself is undetectable in prolactinoma cells. As exogenous LIF suppresses PRL secretion, this pituitary cytokine may be implicated in disordered PRL secretion associated with prolactinomas.


   Acknowledgments
 
We are grateful to Dr. T. Prezant for providing human pituitary tumor RNA samples.


   Footnotes
 
This work was supported by NIH Grant DK 501238, the Doris Factor Molecular Endocrinology Laboratory, and the Annenberg Foundation.

Abbreviations: FBS, Fetal bovine serum; LIF, leukemia inhibitory factor; LIFR, LIF receptor; LPS, lipopolysaccharide; PRL, prolactin; RT, reverse transcriptase; STAT, signal transducer and activator of transcription.

Received August 13, 2002.

Accepted October 18, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Auernhammer CJ, Melmed S 1999 Leukemia inhibitory factor-neuroimmune modulator of endocrine function. Endocr Rev 21:313–345[Abstract/Free Full Text]
  2. Yano H, Readhead C, Nakashima M, Ren SG, Melmed S 1998 Pituitary-directed leukemia inhibitory factor transgene causes Cushing’s syndrome: neuro-immune-endocrine modulation of pituitary development. Mol Endocrinol 12:1708–1720[Abstract/Free Full Text]
  3. Bravo J, Heath JK 2000 Receptor recognition by gp130 cytokines. EMBO J 19:2399–2411[CrossRef][Medline]
  4. Horseman ND, Yu-Lee L-Y 1994 Transcriptional regulation by helix bundle peptide hormone: growth hormone, prolactin, and hematopoietic cytokines. Endocr Rev 15:627–649[Abstract/Free Full Text]
  5. Akita S, Readhead C, Stefaneanu L, Fine J, Tampanaru-Sarmesiu A, Kovacs K, Melmed S 1997 Pituitary-directed leukemia inhibitory factor transgene forms Rathke’s cleft cysts and impairs adult pituitary function. J Clin Invest 99:2462–2469[Medline]
  6. Freeman ME, Kanyicska B, Lerant A, Nagy G 2000 Prolactin: structure, function, and regulation of secretion. Physiol Rev 80:1523–1631[Abstract/Free Full Text]
  7. Molitch ME 2001 Disorders of prolactin secretion. Endocrinol Metab Clin North Am 30:585–610[CrossRef][Medline]
  8. Akita S, Webster J, Ren SG, Takino H, Said J, Zand O, Melmed S 1995 Human and murine pituitary expression of leukemia inhibitory factor. Novel intrapituitary regulation of adrenocorticotropin hormone synthesis and secretion. J Clin Invest 95:1288–1298
  9. Conn PM, Rogers DC 1979 Restoration of responsiveness to gonadotropin releasing hormone (GnRH) in calcium-depleted rat pituitary cells. Life Sci 24:2461–2465[CrossRef][Medline]
  10. Sato K, Watanabe YG 1998 Corticosteroids stimulate the differentiation of growth hormone cells but suppress that of prolactin cells in the fetal rat pituitary. Arch Histol Cytol 61:75–81[Medline]
  11. Chesnokova V, Auernhammer CJ, Melmed S 1998 Murine leukemia inhibitory factor gene disruption attenuates the hypothalamo-pituitary-adrenal axis stress response. Endocrinology 139:2209–2216[Abstract/Free Full Text]
  12. Chesnokova V, Melmed S 2000 Leukemia inhibitory factor mediates the hypothalamic pituitary adrenal axis response to inflammation. Endocrinology 141:4032–4040[Abstract/Free Full Text]
  13. Goiny M, Uvnas-Moberg K, Cekan S 1986 Bromocriptine and apomorphine stimulation of cortisol secretion in conscious dogs; evidence for a stimulatory site located outside the blood brain barrier. Psychopharmacology (Berl) 89:108–112[Medline]
  14. Van Loon GR, Bain J, Ruse JL 1980 Plasma ACTH, cortisol, LH, FSH, testosterone, and dihydrotestosterone responses to bromocriptine in normal men. Arch Androl 4:1–7[Medline]
  15. Thorner MO, Ryan SM, Wass JA, Jones A, Bouloux P, Williams S, Besser GM 1978 Effect of dopamine agonist, largotrile mesylate, on circulating anterior pituitary hormones in man. J Clin Endocrinol Metab 47:372–378[Abstract/Free Full Text]
  16. Parish CL, Finkelstein DI, Drago J, Borrelli E, Horne MK 2001 The role of dopamine receptors in regulating the size of axonal arbors. J Neurosci 21:5147–5157[Abstract/Free Full Text]
  17. Holland FJ, Richards GE, Kaplan SL, Ganong WF, Grumbach MM 1978 The role of biogenic amines in the regulation of growth hormone and corticotropin secretion in the trained conscious dogs. Endocrinology 102:1452–1457[Abstract/Free Full Text]
  18. Uvnäs-Wallensten K, Goiny M, Oriowo MA, Cekan S 1981 Effects of apomorphine and haloperidol on plasma cortisol levels in conscious dogs. Acta Physiol Scand 112:253–256[Medline]
  19. Wilcox CS, Aminoff MJ, Millar JG, Keenan J, Kremer M 1975 Circulating levels of corticotrophin and cortisol after infusions of L-DOPA, dopamine and noradrenaline, in man. Clin Endocrinol (Oxf) 4:191–198[Medline]
  20. Meij BP, Lopes MB, Vance ML, Thorner MO, Laws Jr ER 2000 Double pituitary lesions in three patients with Cushing’s disease. Pituitary 3:159–168[CrossRef][Medline]
  21. Gheri RG, Boddi W, Ammannati F, Olivotto J, Nozzoli C, Franchi A, Bordi L, Luisi ML, Mennonna P 1997 Two-step development of a pituitary adenoma: from hyperprolactinemic syndrome to Cushing’s disease. J Endocrinol Invest 20: 240–244
  22. Barausse M, Attanasio R, Dallabonzana D, Oppizzi G, Veronese S, Lasio G, Valentini LG, Cozzi R 2000 From macroprolactinoma to concomitant ACTH-PRL hypersecretion with Cushing’s disease. J Endocrinol Invest 23: 107–111
  23. Ren SG, Seliktar J, Braunstein GD, Melmed S 1998 Measurement of leukemia inhibitory factor in biological fluids by radioimmunoassay. J Clin Endocrinol Metab 83:1275–1283[Abstract/Free Full Text]
  24. Chesnokova V, Kariagina A, Melmed S 2002 Opposing effects of pituitary leukemia inhibitory factor and SOCS-3 on the ACTH axis response to inflammation. Am J Physiol Endocrinol Metab 282: E1110–E1118
  25. Theas MS, De Laurentis A, Lasaga M, Pisera D, Duvilanski BH, Seilcovich A 1998 Effect of lipopolysaccharide on tumor necrosis factor and prolactin release from rat anterior pituitary cells. Endocrine 8:241–245[CrossRef][Medline]
  26. Chao HS, Poisner AM, Poisner R, Handwerger S 1994 Lipopolysaccharides inhibit prolactin and renin release from human decidual cells. Biol Reprod 50:210–214[Abstract]
  27. Thellin O, Noel G, Khurana S, Ogle CK, Horseman ND 2001 Stress hormone secretion and gut signal transducer (STAT) proteins after burn injury in rats. Shock 16:393–397[Medline]
  28. Nagy E, Berczi I, Wren GE, Asa SL, Kovacs K, 1983 Immunomodulation by bromocriptine. Immunopharmacology 6:231–243[CrossRef][Medline]



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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals