This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Visser-Wisselaar, H. A. Articles by Hofland, L. J. Search for Related Content PubMed PubMed Citation Articles by Visser-Wisselaar, H. A. Articles by Hofland, L. J.

17-ß-Estradiol-Dependent Regulation of Somatostatin Receptor Subtype Expression in the 7315b Prolactin Secreting Rat Pituitary Tumor in Vitro and in Vivo¹

Department of Internal Medicine III, Erasmus University, Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. L. J. Hofland, Department of Internal Medicine III, Room Bd 277, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: hofland{at}inw3.fgg.eur.nl

In the present study, we have investigated the role of estrogens in the regulation of somatostatin receptor subtype (sst) expression in 7315b PRL-secreting rat pituitary tumor cells in vitro and in vivo. sst were undetectable in freshly dispersed cells of the transplantable 7315b tumor. When 7315b cells were cultured in medium containing 10% FCS, the number of high affinity sst increased with prolonged culture time. However, when the medium was supplemented with 10% horse serum (HS) instead of FCS, no sst were detectable on 7315b cells even after three weeks of culturing. In contrast to HS, FCS contains high E₂-levels (HS, 8 pM; FCS, 134 pM).

The antiestrogen tamoxifen (0.5 µM) significantly inhibited the sst number to 50.5% of the value of untreated FCS-grown cells, suggesting that E₂ stimulates sst expression in 7315b rat pituitary tumor cells. E₂ (10 nM) induced a rapid increase in sst number in HS-grown 7315b cells. Octreotide (1 µM) significantly inhibited PRL release and the intracellular PRL concentration of 7315b cells that were cultured in medium supplemented with FCS or with HS + 10 nM E₂ but not in HS alone. This indicates that the sst present on these cells are biologically active. RT-PCR analysis revealed that none of the five currently known sst subtypes were present in freshly dispersed 7315b pituitary tumor cells. The expression of sst₂- and sst₃- messenger RNA (mRNA) was unequivocally correlated to the presence of E₂ because these sst subtypes were detected only in cells that were cultured for 7 and 14 days in medium supplemented with FCS or with HS + 10 nM E₂. sst₁, sst₄ and sst₅ messenger RNA could not be detected.

The 7315b tumor itself synthesizes and secretes huge amounts of PRL. The high PRL levels in tumor-bearing rats inhibit the ovarian E₂-production. No detectable E₂ levels could be measured in the serum of 7315b tumor-bearing rats. The sc administration of 20 µg/day E₂-benzoate normalized the circulating E₂ levels in 7315b tumor-bearing rats. Moreover, E₂-treatment indeed induced sst expression in vivo as shown by ligand binding studies using membrane homogenates and [¹²⁵I-Tyr³]-octreotide as radioligand and by autoradiography on tissue sections. In agreement with the in vitro studies, the expression of the sst₂ subtype was established by RT-PCR analysis in 7315b tumors of E₂-treated rats. However, in contrast to the in vitro studies, E₂-treatment did not effectuate the expression of the sst₃ subtype, suggesting that the in vitro stimulus of E₂ is stronger.

In conclusion: 1) sst₂ and sst₃ expression in the 7315b rat prolactinoma model is primarily dependent upon the presence of estrogens; 2) the antihormonal action of octreotide in 7315b tumor cells in vitro is mediated via the sst₂ and/or sst₃ subtypes; 3) the absence of sst expression in vivo can be explained by the hormonal environment of the 7315b tumor cells. The 7315b tumor cells in vivo may down-regulate their own receptor status via their host, because of the ensuing hyperprolactinemia results in a hypo-estrogenic state.

This article has been cited by other articles:

				M. Paez-Pereda, D. Giacomini, D. Refojo, A. C. Nagashima, U. Hopfner, Y. Grubler, A. Chervin, V. Goldberg, R. Goya, S. T. Hentges, et al. Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk PNAS, February 4, 2003; 100(3): 1034 - 1039. [Abstract] [Full Text] [PDF]

				L. J. Hofland and S. W. J. Lamberts The Pathophysiological Consequences of Somatostatin Receptor Internalization and Resistance Endocr. Rev., February 1, 2003; 24(1): 28 - 47. [Abstract] [Full Text] [PDF]

				V. A. Dalm, P. M. van Hagen, P. M. van Koetsveld, A. W. Langerak, A.-J. van der Lely, S. W. Lamberts, and L. J. Hofland Cortistatin Rather Than Somatostatin as a Potential Endogenous Ligand for Somatostatin Receptors in the Human Immune System J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 270 - 276. [Abstract] [Full Text] [PDF]

				W. A.P. Breeman, M. de Jong, J. L. Erion, J. E. Bugaj, A. Srinivasan, B. F. Bernard, D. J. Kwekkeboom, T. J. Visser, and E. P. Krenning Preclinical Comparison of 111In-Labeled DTPA- or DOTA-Bombesin Analogs for Receptor-Targeted Scintigraphy and Radionuclide Therapy J. Nucl. Med., December 1, 2002; 43(12): 1650 - 1656. [Abstract] [Full Text] [PDF]

				L. S. Farhy, M. Straume, M. L. Johnson, B. Kovatchev, and J. D. Veldhuis Unequal autonegative feedback by GH models the sexual dimorphism in GH secretory dynamics Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2002; 282(3): R753 - R764. [Abstract] [Full Text] [PDF]

				M. J. Bray, T. M. Vick, N. Shah, S. M. Anderson, L. W. Rice, A. Iranmanesh, W. S. Evans, and J. D. Veldhuis Short-Term Estradiol Replacement in Postmenopausal Women Selectively Mutes Somatostatin's Dose-Dependent Inhibition of Fasting Growth Hormone Secretion J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3143 - 3149. [Abstract] [Full Text] [PDF]

				M. E. Freeman, B. Kanyicska, A. Lerant, and G. Nagy Prolactin: Structure, Function, and Regulation of Secretion Physiol Rev, October 1, 2000; 80(4): 1523 - 1631. [Abstract] [Full Text] [PDF]

				E. E. Muller, V. Locatelli, and D. Cocchi Neuroendocrine Control of Growth Hormone Secretion Physiol Rev, April 1, 1999; 79(2): 511 - 607. [Abstract] [Full Text] [PDF]

				D. Djordjijevic, J. Zhang, M. Priam, C. Viollet, D. Gourdji, C. Kordon, and J. Epelbaum Effect of 17{beta}-Estradiol on Somatostatin Receptor Expression and Inhibitory Effects on Growth Hormone and Prolactin Release in Rat Pituitary Cell Cultures Endocrinology, May 1, 1998; 139(5): 2272 - 2277. [Abstract] [Full Text] [PDF]

				N. Kimura, S. Tomizawa, K. N. Arai, and N. Kimura Chronic Treatment with Estrogen Up-Regulates Expression of sst2 Messenger Ribonucleic Acid (mRNA) but Down-Regulates Expression of sst5 mRNA in Rat Pituitaries Endocrinology, April 1, 1998; 139(4): 1573 - 1580. [Abstract] [Full Text] [PDF]