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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 12 4652-4655
Copyright © 1999 by The Endocrine Society

Original Studies

Expression of Prolactin-Releasing Peptide and Its Receptor Messenger Ribonucleic Acid in Normal Human Pituitary and Pituitary Adenomas1

Xun Zhang, Daniel C. Danila, Miyuki Katai, Brooke Swearingen and Anne Klibanski

Neuroendocrine Unit, Departments of Medicine and Neurosurgery (B.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Anne Klibanski, M.D., Neuroendocrine Unit, BUL 457B, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The recently identified PRL-releasing peptide (PrRP) is the first hypothalamic peptide hormone that specifically stimulates PRL production from the pituitary gland. Similar to other hypothalamic regulatory hormones, it acts through its specific seven-transmembrane domain, G protein-coupled receptor. Using RT-PCR, we examined messenger ribonucleic acid (mRNA) expression of PrRP and its receptor in normal human pituitary tissue and in pituitary tumors. PrRP mRNA was expressed in all five normal pituitary glands examined. In contrast, PrRP mRNA was detected in only 5 of 11 of the human prolactinomas. All 5 prolactinomas expressing PrRP were responsive to dopamine agonist treatment, whereas PrRP-negative prolactinomas were non- or partially responsive. PrRP mRNA was also detected in 6 of 13 GH-secreting tumors and 5 of 10 clinically nonfunctioning tumors investigated. PrRP receptor mRNA was found in all the normal and neoplastic human pituitary samples studied. The production of PrRP and its receptor by normal and neoplastic pituitary tissue raises the question of whether it may regulate PRL production in an autocrine/paracrine manner in pituitary tissue. Further investigation of PrRP and its receptor expression and function will be needed to clarify its potential role in regulating PRL secretion in normal human lactotrophs and pituitary tumors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IN CONTRAST to other anterior pituitary hormones for which a specific hypothalamic releasing factor has been documented, until recently no hypothalamic peptide hormone was found to specifically stimulate PRL secretion. Instead, PRL has been shown to be primarily regulated by chronic dopaminergic inhibition. The actions of the hypothalamic peptide-releasing hormones as well as dopamine are mediated by their specific receptors that contain seven transmembrane domains and couple with guanine nucleotide-binding proteins (G proteins). Recently, Hinuma et al. cloned a novel G protein-coupled receptor from pituitary tissue and then identified its hypothalamic ligand, PRL-releasing peptide (PrRP) (1). Although its biological significance remains unknown, this peptide specifically stimulates PRL secretion from pituitary tissue in both in vitro and in vivo assays and does not affect the secretion of other anterior pituitary hormones, such as GH, FSH, LH, TSH, and ACTH. This peptide represents a new PRL-stimulating peptide hormone of hypothalamic origin.

Although normal pituitary cell growth and hormone secretion are regulated by hypothalamic hormones and other factors, evidence has shown that pituitary tumors are derived from somatic mutations leading to clonal cell expansion (2, 3). Hormone secretion from pituitary tumors is usually independent of hypothalamic control, and the factors leading to neoplastic proliferation of a single mutated cell are as yet unknown (4). Many hormones may function in an autocrine/paracrine manner to mediate local actions. For example, GnRH has been shown to be produced by normal pituitary and gonadotroph tumors, suggesting the possibility of an autocrine/paracrine role in the regulation of cell function and tumor phenotype (5). PRL has also been demonstrated to be synthesized by reproductive tissues and the immune system to mediate local actions, such as antibody production and lymphocyte proliferation (6). The newly identified PrRP may represent a novel autocrine/paracrine mediator of PRL regulation and cell proliferation in PRL-producing adenomas. We therefore investigated messenger ribonucleic acid (mRNA) expression of PrRP and its receptor in normal human pituitary tissue and in human pituitary adenomas using RT-PCR. Our results revealed that PrRP mRNA is expressed in all normal human pituitary glands examined. However, it is only expressed in about 50% of pituitary tumors, although the expression of its receptor mRNA is ubiquitous. The PRL-secreting tumors that express PrRP mRNA are responsive to dopamine agonist treatment. In contrast, those prolactinomas that were negative for PrRP mRNA were either nonresponsive or partially responsive to the treatment, suggesting that a common mechanism may exist between PrRP expression and responsiveness to dopamine agonist treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients

Thirty-four pituitary tumors were obtained in 0.9% saline after transsphenoidal surgery and immediately frozen in liquid nitrogen before analysis. The study was approved by the Massachusetts General Hospital subcommittee for human studies. The diagnosis was established by clinical, biochemical, and radiological findings and was confirmed by immunohistochemistry after surgery. Patients having clinically nonfunctioning tumors were classified based on the presence of a macroadenoma without a diagnosis of acromegaly or Cushing’s disease and with serum PRL levels of less than 100 µg/L. Serum {alpha}-subunit concentrations were within normal limits in all patients. Insulin-like growth factor I levels were elevated in all patients with acromegaly. In patients with prolactinomas or clinically nonfunctioning tumors, serum insulin-like growth factor I levels were within the normal range. Immunohistochemical analysis of tumor sections revealed that all patients with prolactinomas had positive immunocytochemical staining for PRL, and all patients with acromegaly had positive staining for GH. In nonfunctioning tumors, immunocytochemical staining was negative for PRL, GH, and ACTH, but positive for glycoprotein hormone subunits {alpha}, FSHß, and/or LHß and, in one tumor, TSHß. Five normal pituitary glands and three medulla oblongata were obtained 2–16 h postmortem from the Harvard Brain Tissue Resource Center (Belmont, MA). Tissue specimens were snap-frozen in liquid nitrogen before analysis.

Total RNA preparation

Total RNA from human pituitary tumors and normal pituitary glands were prepared using Trizol reagent (Life Technologies, Inc., Gaithersburg, MD). Approximately, 100 mg tissue sample were homogenized in 1 mL Trizol reagent and incubated at room temperature for 5 min, followed by chloroform extraction and isopropyl alcohol precipitation.

RT-PCR

RT was performed using the Reverse Transcription System (Promega Corp., Madison, WI) according to the manufacturer’s protocol. One microgram of total RNA was treated with 10 U ribonuclease-free deoxyribonuclease (Stratagene, La Jolla, CA) to eliminate genomic DNA contamination, and reverse transcribed with oligo(deoxythymidine) primer. RT-negative reactions performed in the absence of reverse transcriptase were also included to assure the lack of gemonic contamination. After RT, the samples were amplified with Taq DNA polymerase [Promega Corp. or QIAGEN (Valencia, CA)] in the presence of [{alpha}-32P]deoxy (d)-CTP (Amersham Pharmacia Biotech, Piscataway, NJ), using human PrRP-specific primers, 5'-GTCGTACCCATCGGCAC-TCC-3' and 5'-CGACATAGCACCGCCTTCCA-3'; human PrRP receptor-specific primers, 5'-ATGGCCTCATCGACCACTCGGGGCCCCAGG-3' and 5'-CGCCGCCGAACACCCAGCCGCGTGGCTC-3'; and human cyclophilin A-specific primers, 5'-CATGGTCAACCCCACCGTGTTCTT-3' and 5'-TAGATGGACTTGCCACCAGTGCCAT-3', as an internal control. The amplified DNA fragments for PrRP, PrRP receptor, and cyclophilin A are 182, 394, and 240 bp, respectively. The samples from normal pituitary glands and at least one type of pituitary adenoma were always used together in one set of PCR reactions. Each PCR reaction contained 1 µl RT product, 10 pmol of each primer, 2.5 µCi [{alpha}-32P]dCTP, 200 µmol/L of each dNTP, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 9.0), 1.5 mmol/L MgCl2, 0.1% Triton X-100, and 2.5 U Taq polymerase in a final volume of 100 µl. PCR reactions were carried out at 94 C for 1 min, 60 C for 1 min, and 72 C for 1.5 min for 40 cycles. PCR products were analyzed by electrophoresis in 6% sequencing gel with the SequaGel System (National Diagnostics, Atlanta, GA) and exposed to BioMax-MS film (Eastman Kodak Co., Rochester, NY). Each RT and PCR reaction was repeated at least three times to assure reliable reproducibility. To confirm the identities of amplified DNA fragments, PCR reactions were carried out in the absence of [32P]dCTP. After amplification, six randomly picked DNA samples were gel purified with the QIAEX II Gel Extraction System (QIAGEN) and subjected to sequence analysis with PrRP- or PrRP receptor-specific primers, using the Thermo Sequenase-radiolabeled terminator cycle sequencing kit (Amersham Pharmacia Biotech, Piscataway, NJ).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Using RT-PCR, PrRP mRNA was detected in all five normal human pituitary glands examined (Fig. 1AGo) as well as in control medulla tissue (1). In addition, PrRP receptor mRNA was detected in these pituitary samples, although no receptor mRNA was found in medulla (Fig. 1BGo).



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  		Figure 1. PrRP and receptor mRNA expression in normal pituitary. Five normal pituitary glands were examined. A medulla sample (M) was used as the positive control for PrRP. Products from RT carried out in the presence (+) or absence (-) of reverse transcriptase were used as templates in PCR reaction. A, PCR products with PrRP-specific primers. B, PCR products with PrRP receptor-specific primers. C, PCR products with cyclophilin A-specific primers as an internal control for RNA integrity.

 
We next examined PrRP and receptor mRNA expression in 11 PRL-secreting, 13 GH-secreting, and 10 clinically nonfunctioning human pituitary tumors. The clinical characteristics and status of PrRP and receptor expression are summarized in Tables 1–3GoGoGo. Representative PCR results are shown in Figs. 2–4GoGoGo. Among 11 prolactinomas, 5 of them expressed PrRP mRNA (Fig. 2AGo, lanes 3, 4, 7, 9, and 10). All 5 of these tumors were responsive to dopamine agonist treatment, defined as PRL suppression of more than 90% or normalization of serum PRL concentration during therapy. In these 5 patients surgery was performed because of an inability to tolerate long term dopamine agonist therapy. The 5 PrRP-negative prolactinomas were nonresponsive or partially responsive, as defined by less than 90% decrease and no normalization of serum PRL levels during prolonged treatment. Two additional patients with PrRP-negative tumors were untreated due to a large cystic component or apoplexy. PrRP mRNA was also detected in 6 of 13 GH-secreting tumors (Fig. 3AGo, lanes 1, 2, 3, 6, 7, and 10) and 5 of 10 nonfunctioning tumors (Fig. 4AGo, lanes 1, 3, 6, 7, and 8). In contrast, PrRP receptor mRNA was expressed in all the tumors (Figs. 2BGo, 3BGo, and 4BGo), except for one nonfunctioning tumor (Fig. 4BGo, lane 1). Cyclophilin A mRNA was also detected in each tumor sample as a positive control (Figs. 2CGo, 3CGo, and 4CGo). Comparative RT-PCR (7, 8, 9) revealed that the expression levels of PrRP mRNA in normal pituitary glands and tumors were relatively similar, and the levels of PrRP receptor mRNA expression varied among samples (data not shown).


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  		Table 1. Clinical data for patients with PRL-secreting tumors

 

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  		Table 2. Clinical data for patients with GH-secreting pituitary tumors

 

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  		Table 3. Clinical data for patients with clinical nonfunctioning pituitary tumors

 


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  		Figure 2. A representative RT-PCR result showing PrRP and its receptor mRNA expression in 11 PRL-secreting pituitary adenomas. Only PCR products from the RT (+) reaction are shown. A, PrRP; B, PrRP receptor; C, cyclophilin A.

 


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  		Figure 3. A representative RT-PCR result showing PrRP and its receptor mRNA expression in 13 GH-secreting pituitary adenomas. Only PCR products from the RT (+) reaction are shown. A, PrRP; B, PrRP receptor; C, cyclophilin A.

 


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  		Figure 4. A representative RT-PCR result showing PrRP and its receptor mRNA expression in 10 clinically nonfunctioning pituitary adenomas. Only PCR products from RT (+) reaction are shown. A, PrRP; B, PrRP receptor; C, cyclophilin A.

 
To confirm the identities of PCR-amplified DNA fragments, six fragments were randomly picked to be analyzed by direct sequencing. The PCR products were identified as PrRP or PrRP receptor complementary DNA fragments by comparison to the published sequences in GenBank.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We show, for the first time, that PrRP mRNA is expressed in the normal human pituitary gland as well as in approximately half of pituitary adenomas. Expression of PrRP receptor mRNA in human pituitary is consistent with the hypothesis that the pituitary is the target gland for PrRP action. However, expression of PrRP mRNA itself in pituitary tissue raises the question of whether it may function in an autocrine/paracrine manner to regulate PRL production directly at the level of pituitary. A number of hormones have been shown to be able to act both systemically and locally at a tissue level. For example, although ovarian activin and inhibin regulate pituitary FSH production, they also act in reproductive tissue to affect cell proliferation and differentiation (10, 11, 12). Moreover, activin is produced locally by the pituitary to regulate anterior pituitary cell proliferation (13, 14). We have now shown that PrRP mRNA can be produced by the pituitary, and its local action needs to be further investigated.

It is important to note that in contrast to its receptor, PrRP is only expressed in a subset of each type of pituitary adenoma (nonfunctioning, PRL secreting, and GH secreting). It is unknown whether the lack of PrRP expression in a large percentage of pituitary tumors is related to any mechanism of pituitary tumor pathogenesis. One possibility would be that this gene is linked to a cell growth-related gene that is commonly mutated in pituitary tumors. In contrast to PrRP, its receptor mRNA is prevalently expressed in all human pituitary tumors. Although the abundance of PrRP receptor mRNA is variable among tumors, no correlation was observed between the presence of PrRP mRNA and the expression level of its receptor mRNA. Therefore, the transcription of PrRP and that of its receptor are probably differentially regulated.

We found that among 11 PRL-overproducing tumors, only 5 expressed PrRP mRNA (45%). Also, markedly increased PrRP mRNA levels were not observed in these tumors compared to those in normal pituitary tissue by comparative RT-PCR (data not shown). These results suggest that although one of the physiological functions of PrRP is to stimulate PRL production, local expression of PrRP in pituitary is unlikely to be a fundamental determinant for PRL overproduction in prolactinomas. However, we cannot exclude the possibility that the presence of mutations in PrRP and its receptor may be responsible for the overproduction of PRL in a subset of tumors. Similar mutations have been observed in different systems (15, 16, 17) and in particular have been identified in G protein-coupled receptors (18, 19), causing endocrine disorders.

We noticed that all five PrRP-positive prolactinomas were responsive to dopamine agonist treatment, as defined by more than 90% suppression or normalization of serum PRL levels. In contrast, the PrRP-negative prolactinomas studied were nonresponsive or partially responsive. As shown in Table 1Go, the PRL levels in patients 3, 4, and 10 were restored to within or near the normal range (0–15 µg/L) during dopamine agonist treatment, and PrRP mRNA was detected in these tumors. In patients 7 and 9, more than 90% suppression of PRL was observed during treatment, and the tumors are also positive for PrRP mRNA. In one patient (no. 1), the tumor was resistant to dopamine agonist treatment, and no PrRP mRNA was detected in the tumor, whereas in three tumors (no. 5, 8, and 11), medical treatment caused only a partial decrease in the serum PRL concentration without normalization, and no further suppression was observed with prolonged treatment. These patients were considered partially responsive, and these tumors are also negative for PrRP mRNA. It is important to note that the numbers of dopamine responsive vs. nonresponsive tumors are small. In addition, clinical responsiveness to dopamine agonist is difficult to interpret because of drug tolerance and surgical bias. Therefore, confirmation of this observation in a large number of tumors will be critical. Nevertheless, these preliminary data raise the possibility that the expression of PrRP may be related to dopaminergic regulatory mechanisms. It has been reported that dopamine receptor expression is reduced in nonresponsive prolactinomas (20). G proteins, adenylyl cyclase, and the transcription factor Pit-1 have also been suggested to be involved in dopamine-mediated signal transduction in lactotroph cells (21). The potential relationship between expression of dopamine receptor, PrRP, and other factors remains to be further explored in a larger set of tumors. This is the first report of PrRP and receptor mRNA expression in normal and neoplastic human pituitaries. Because PrRP is a newly identified regulatory molecule, its physiological function and significance remain unknown at this time. Further study will be needed to understand the potential roles of PrRP and its receptor in local regulation of hormone production and cell proliferation in normal pituitary and PRL-secreting adenomas.


   Acknowledgments
 
We thank the Harvard Brain Tissue Resource Center for providing normal pituitary and medulla oblongata samples.


   Footnotes
 
1 This work was supported in part by NIH Grant R01-DK-40947 and the Jarislowski Foundation. The Harvard Brain Tissue Resource Center was supported in part by PHS Grant MH/NS 31862. Back

Received May 24, 1999.

Revised July 15, 1999.

Accepted August 26, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  8. Varadi A, Molnar E, Ostenson C-G, Ashcroft, SJH. 1996 Isoforms of endoplasmic reticulum Ca2+-ATPase are differentially expressed in normal and diabetic islets of Langerhans. Biochem J. 319:521–527.
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  10. Gonzalez-Manchon C, Vale W. 1989 Activin A, inhibin, and transforming growth factor-ß modulate growth of two gonadal cell lines. Endocrinology. 125:1666–1672.[Abstract]
  11. Mather J, Attie K, Woodruff TK, Rice G, Phillips D. 1990 Activin stimulates spermatogonial proliferation in germ-Sertoli cell cocultures from immature rat testis. Endocrinology. 127:3206–3214.[Abstract]
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