Abstract
Aromatase, a key enzyme in local estrogen synthesis, is expressed in different pituitary tumors including growth hormone (GH)-secreting adenomas. We aimed to evaluate aromatase, estrogen receptor α (ERα), estrogen receptor β (ERβ), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) expressions in GH-secreting adenomas, and investigate their correlation with clinical, pathologic, and radiologic parameters. This cross-sectional study was conducted in a tertiary center in Turkey. Protein expressions were determined via immunohistochemical staining in ex vivo tumor samples of 62 patients with acromegaly and ten normal pituitary tissues. Concordantly increased aromatase, PTTG, and FGF2 expressions were detected in the tumor samples as compared with controls (p < 0.001 for all). None of the tumors expressed ERα while ERβ was detected only in mixed somatotroph adenomas. Aromatase, ERβ, PTTG expressions were not significantly different between patients with and without remission (p > 0.05 for all). FGF2 expression was significantly higher in patients without postoperative and late remission (p = 0.002 and p = 0.012, respectively), with sphenoid bone invasion, optic chiasm compression, and somatostatin analog resistance (p = 0.005, p = 0.033, and p = 0.013, respectively). Aromatase, PTTG and FGF2 expressions were positively correlated with each other (r = 0,311, p = 0.008 for aromatase, FGF2; r = 0.380, p = 0.001 for aromatase, PTTG; r = 0.400, p = 0.001 for FGF2, PTTG). PTTG-mediated FGF2 upregulation is associated with more aggressive tumor features in patients with acromegaly. Also, locally produced estrogen through aromatization might have a role in this phenomenon.
Similar content being viewed by others
References
T. Minematsu, S. Miyai, H. Kajiya, M. Suzuki, N. Sanno, S. Takekoshi, A. Teramoto, R.Y. Osamura, Recent progress in studies of pituitary tumor pathogenesis. Endocrine 28(1), 37–41 (2005). doi:10.1385/endo:28:1:037
S. Melmed, Mechanisms for pituitary tumorigenesis: the plastic pituitary. J. Clin. Invest. 112(11), 1603–1618 (2003). doi:10.1172/jci20401
M. Pawlikowski, Endocrine/paracrine control of pituitary cell proliferation and its involvement in pituitary tumorigenesis. Pituitary 1(3–4), 251–256 (1999). doi:10.1023/A:1009998207652
A.S. Caglar, A. Kapucu, K.A. Dar, H.M. Ozkaya, E. Caglar, H. Ince, P. Kadioglu, Localization of the aromatase enzyme expression in the human pituitary gland and its effect on growth hormone, prolactin, and thyroid stimulating hormone axis. Endocrine (2015). doi:10.1007/s12020-015-0537-6
D. Avtanski, H.J. Novaira, S. Wu, C.J. Romero, R. Kineman, R.M. Luque, F. Wondisford, S. Radovick, Both estrogen receptor α and β stimulate pituitary GH gene expression. Mol. Endocrinol. 28(1), 40–52 (2014). doi:10.1210/me.2013-1245
T. Spady, R. McComb, J. Shull, Estrogen action in the regulation of cell proliferation, cell survival, and tumorigenesis in the rat anterior pituitary gland. Endocrine 11(3), 217–233 (1999). doi:10.1385/ENDO:11:3:217
F. Salehi, K. Kovacs, B.W. Scheithauer, R.V. Lloyd, M. Cusimano, Pituitary tumor-transforming gene in endocrine and other neoplasms: a review and update. Endocr. Relat. Cancer 15(3), 721–743 (2008). doi:10.1677/erc-08-0012
C.J. McCabe, A.P. Heaney, Pituitary tumour transforming gene in endocrine cancer. Clin. Endocrinol. 58(6), 673–682 (2003). doi:10.1046/j.1365-2265.2003.01687.x
T.R. Prezant, P. Kadioglu, S. Melmed, An intronless homolog of human proto-oncogene hPTTG is expressed in pituitary tumors: evidence for hPTTG family. J. Clin. Endocrinol. Metab. 84(3), 1149–1152 (1999). doi:10.1210/jcem.84.3.5658
A.J. Weissberger, K.K. Ho, Activation of the somatotropic axis by testosterone in adult males: evidence for the role of aromatization. J. Clin. Endocrinol. Metab. 76(6), 1407–1412 (1993). doi:10.1210/jcem.76.6.8501143
M. Iruthayanathan, Y.H. Zhou, G.V. Childs, Dehydroepiandrosterone restoration of growth hormone gene expression in aging female rats, in vivo and in vitro: evidence for actions via estrogen receptors. Endocrinology 146(12), 5176–5187 (2005). doi:10.1210/en.2005-0811
J. Carretero, G. Vazquez, E. Blanco, M. Rubio, M. Santos, A. Martin-Clavijo, J.L. Torres, R. Vazquez, Immunohistochemical evidence of the presence of aromatase P450 in the rat hypophysis. Cell Tissue Res. 295(3), 419–423 (1999)
J. Carretero, D.J. Burks, G. Vazquez, M. Rubio, E. Hernandez, P. Bodego, R. Vazquez, Expression of aromatase P450 is increased in spontaneous prolactinomas of aged rats. Pituitary 5(1), 5–10 (2002)
P. Kadioglu, G. Oral, M. Sayitoglu, N. Erensoy, B. Senel, N. Gazioglu, A. Sav, G. Cetin, U. Ozbek, Aromatase cytochrome P450 enzyme expression in human pituitary. Pituitary 11(1), 29–35 (2008). doi:10.1007/s11102-007-0065-3
H. Akinci, A. Kapucu, K.A. Dar, O. Celik, B. Tutunculer, G. Sirin, B. Oz, N. Gazioglu, H. Ince, S. Aliustaoglu, P. Kadioglu, Aromatase cytochrome P450 enzyme expression in prolactinomas and its relationship to tumor behavior. Pituitary 16(3), 386–392 (2013). doi:10.1007/s11102-012-0436-2
A. Selek, B. Cetinarslan, Y. Gurbuz, I. Tarkun, Z. Canturk, B. Cabuk, Aromatase enzyme expression in acromegaly and its possible relationship with disease prognosis. Endocrine 49(1), 250–257 (2015). doi:10.1007/s12020-014-0445-1
P.H. Gonzales, L.C. Mezzomo, N.P. Ferreira, A.V. Roehe, M.B. Kohek, C. Oliveira, Mda, Aromatase P450 expression in human pituitary adenomas. Neuropathology 35(1), 16–23 (2015). doi:10.1111/neup.12145
E. Hatipoglu, S. Bozcan, P. Kadioglu, Discontinuation of somatostatin analogs while acromegaly is in long-term remission. Pituitary 18(4), 554–560 (2015). doi:10.1007/s11102-014-0608-3
L. Katznelson, E.R. Laws Jr, S. Melmed, M.E. Molitch, M.H. Murad, A. Utz, J.A. Wass, Acromegaly: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 99(11), 3933–3951 (2014). doi:10.1210/jc.2014-2700
A. Colao, R.S. Auriemma, G. Lombardi, R. Pivonello, Resistance to somatostatin analogs in acromegaly. Endocr. Rev. 32(2), 247–271 (2011). doi:10.1210/er.2010-0002
V. Birzniece, A. Sata, S. Sutanto, K.K. Ho, Paracrine regulation of growth hormone secretion by estrogen in women. J. Clin. Endocrinol. Metab. 95(8), 3771–3776 (2010). doi:10.1210/jc.2010-0476
G. Vlotides, T. Eigler, S. Melmed, Pituitary tumor-transforming gene: physiology and implications for tumorigenesis. Endocr. Rev. 28(2), 165–186 (2007). doi:10.1210/er.2006-0042
X. Zhang, G.A. Horwitz, A.P. Heaney, M. Nakashima, T.R. Prezant, M.D. Bronstein, S. Melmed, Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J. Clin. Endocrinol. Metab. 84(2), 761–767 (1999). doi:10.1210/jcem.84.2.5432
C.J. McCabe, J.S. Khaira, K. Boelaert, A.P. Heaney, L.A. Tannahill, S. Hussain, R. Mitchell, J. Olliff, M.C. Sheppard, J.A. Franklyn, N.J. Gittoes, Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour. Clin. Endocrinol. (Oxf) 58(2), 141–150 (2003)
M. Filippella, F. Galland, M. Kujas, J. Young, A. Faggiano, G. Lombardi, A. Colao, G. Meduri, P. Chanson, Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas: a clinical and immunohistochemical study. Clin. Endocrinol. (Oxf) 65(4), 536–543 (2006). doi:10.1111/j.1365-2265.2006.02630.x
F. Salehi, K. Kovacs, B.W. Scheithauer, D. Cantelmi, E. Horvath, R.V. Lloyd, M. Cusimano, Immunohistochemical expression of pituitary tumor transforming gene (PTTG) in pituitary adenomas: a correlative study of tumor subtypes. Int. J. Surg. Pathol. 18(1), 5–13 (2010). doi:10.1177/1066896909356105
T. Minematsu, N. Egashira, H. Kajiya, M. Takei, S. Takekoshi, Y. Itoh, H. Tsukamoto, J. Itoh, N. Sanno, A. Teramoto, R.Y. Osamura, PTTG is a secretory protein in human pituitary adenomas and in mouse pituitary tumor cell lines. Endocr. Pathol. 18(1), 8–15 (2007)
A. Wierinckx, C. Auger, P. Devauchelle, A. Reynaud, P. Chevallier, M. Jan, G. Perrin, M. Fèvre-Montange, C. Rey, D. Figarella-Branger, G. Raverot, M.-F. Belin, J. Lachuer, J. Trouillas, A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr. Relat. Cancer 14(3), 887–900 (2007). doi:10.1677/erc-07-0062
A.P. Heaney, G.A. Horwitz, Z. Wang, R. Singson, S. Melmed, Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis. Nat. Med. 5(11), 1317–1321 (1999). doi:10.1038/15275
K. Chamaon, D. Kanakis, C. Mawrin, K. Dietzmann, E. Kirches, Transcripts of PTTG and growth factors bFGF and IGF-1 are correlated in pituitary adenomas. Exp. Clin. Endocrinol. Diabetes 118(2), 121–126 (2010). doi:10.1055/s-0029-1215588
A.P. Heaney, M. Fernando, S. Melmed, Functional role of estrogen in pituitary tumor pathogenesis. J. Clin. Invest. 109(2), 277–283 (2002). doi:10.1172/jci14264
Y. Lu, M. You, Z. Ghazoui, P. Liu, P.T. Vedell, W. Wen, A.M. Bode, C.J. Grubbs, R.A. Lubet, Concordant effects of aromatase inhibitors on gene expression in ER + Rat and human mammary cancers and modulation of the proteins coded by these genes. Cancer Prev. Res. 6(11), 1151–1161 (2013). doi:10.1158/1940-6207.capr-13-0126
M. Schmidt, G. Löffler, Induction of aromatase in stromal vascular cells from human breast adipose tissue depends on cortisol and growth factors. FEBS Lett. 341(2–3), 177–181 (1994). doi:10.1016/0014-5793(94)80452-4
K. Gill, N. Kirma, R.R. Tekmal, Overexpression of aromatase in transgenic male mice results in the induction of gynecomastia and other biochemical changes in mammary glands. J. Steroid Biochem. Mol. Biol. 77(1), 13–18 (2001)
G. Vlotides, Y.H. Chen, T. Eigler, S.G. Ren, S. Melmed, Fibroblast growth factor-2 autofeedback regulation in pituitary folliculostellate TtT/GF cells. Endocrinology 150(7), 3252–3258 (2009). doi:10.1210/en.2008-1625
S. Oomizu, K. Chaturvedi, D.K. Sarkar, Folliculostellate cells determine the susceptibility of lactotropes to estradiol’s mitogenic action. Endocrinology 145(3), 1473–1480 (2004). doi:10.1210/en.2003-0965
H.B. Fokidis, H.H. Adomat, G. Kharmate, E. Hosseini-Beheshti, E.S. Guns, K.K. Soma, Regulation of local steroidogenesis in the brain and in prostate cancer: lessons learned from interdisciplinary collaboration. Front. Neuroendocrinol. 36, 108–129 (2015). doi:10.1016/j.yfrne.2014.08.005
B. Filova, M. Malinova, J. Babickova, L. Tothova, D. Ostatnikova, P. Celec, J. Hodosy, Effects of testosterone and estradiol on anxiety and depressive-like behavior via a non-genomic pathway. Neurosci. Bull. 31(3), 288–296 (2015). doi:10.1007/s12264-014-1510-8
T. Suzuki, H. Sasano, H. Sasaki, T. Fukaya, H. Nagura, Quantitation of P450 aromatase immunoreactivity in human ovary during the menstrual cycle: relationship between the enzyme activity and immunointensity. J. Histochem. Cytochem. 42(12), 1565–1573 (1994)
Acknowledgments
This study did not receive any specific grants from any funding agencies in the public, commercial, or not-for-profit sector.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Rights and permissions
About this article
Cite this article
Ozkaya, H.M., Comunoglu, N., Keskin, F.E. et al. Locally produced estrogen through aromatization might enhance tissue expression of pituitary tumor transforming gene and fibroblast growth factor 2 in growth hormone-secreting adenomas. Endocrine 52, 632–640 (2016). https://doi.org/10.1007/s12020-015-0802-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-015-0802-8