Skip to main content

ERα, but not ERβ and GPER, Mediates Estradiol-Induced Secretion of TSH in Mouse Pituitary

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

Although estradiol (E2) plays a critical role in the promotion of pituitary development and in the regulation of various pituitary hormones, its effects on the thyroid-stimulating hormone (TSH) remain unaddressed. The actions of E2 are mediated by two classical nuclear estrogen receptors α (ERα) and β (ERβ) and the G protein-coupled estrogen receptor (GPER). However, the types of estrogen receptor involvement in the regulation of thyrotropes are still limited. In this study, we demonstrate that ERα, but not ERβ and GPER, is localized to thyrotropes in the pituitary of female mouse. In agreement with the presence of ERα in thyrotropes, E2 was shown to stimulate TSH release in vitro from primary culture of female mouse pituitary cells. PPT, a ERα-selective agonist, but not DPN (a ERβ-selective agonist) and G-1 (a GPER-selective agonist), was shown to stimulate TSH release in mouse pituitary cells. This effect could be prevented by the specific ER antagonist fulvestrant and the selective ERα antagonist MPP. The findings of this study suggest that E2 may bind to ERα to trigger TSH release and provide novel information on the differential regulation of multiple estrogen receptors in the pituitary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

The datasets generated or analyzed during the current study are presented in the manuscript and are available from the corresponding author upon reasonable request.

Code Availability

Not applicable.

References

  1. Katzenellenbogen, B. S., Montano, M. M., Ediger, T. R., Sun, J., Ekena, K., Lazennec, G. … Katzenellenbogen, J. A. (2000). Estrogen receptors: selective ligands, partners, and distinctive pharmacology. Recent Progress in Hormone Research, 55, 163–195

    CAS  PubMed  Google Scholar 

  2. Nilsson, S., Mäkelä, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G. … Gustafsson, J. A. (2001). Mechanisms of estrogen action. Physiological Reviews, 81(4), 1535–1565

    Article  CAS  Google Scholar 

  3. De Francesco, E. M., Sotgia, F., Clarke, R. B., Lisanti, M. P., & Maggiolini, M. (2017). G protein-coupled receptors at the crossroad between physiologic and pathologic angiogenesis: old paradigms and emerging concepts. International Journal of Molecular Sciences, 18(12), 2713

    Article  Google Scholar 

  4. Zimmerman, M. A., Budish, R. A., Kashyap, S., & Lindsey, S. H. (2016). GPER-novel membrane oestrogen receptor. Clinical Science (London, England: 1979), 130(12), 1005–1016

  5. Levin, E. R., & Hammes, S. R. (2016). Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors. Nature Reviews Molecular Cell Biology, 17(12), 783–797

    Article  CAS  Google Scholar 

  6. Christian, H. C., & Morris, J. F. (2002). Rapid actions of 17beta-oestradiol on a subset of lactotrophs in the rat pituitary. The Journal of physiology, 539(Pt 2), 557–566

    Article  CAS  Google Scholar 

  7. Beardwell, C., & Robertson, G. L. (Eds.). (1981). The Pituitary, Butterworths, London and Boston, pp. 337

  8. Seilicovich, A. (2010). Cell life and death in the anterior pituitary gland: role of oestrogens. Journal of Neuroendocrinology, 22(7), 758–764

    CAS  PubMed  Google Scholar 

  9. González, M., Reyes, R., Damas, C., Alonso, R., & Bello, A. R. (2008). Oestrogen receptor alpha and beta in female rat pituitary cells: an immunochemical study. General and Comparative Endocrinology, 155(3), 857–868

    Article  Google Scholar 

  10. Mitchner, N. A., Garlick, C., & Ben-Jonathan, N. (1998). Cellular distribution and gene regulation of estrogen receptors alpha and beta in the rat pituitary gland. Endocrinology, 139(9), 3976–3983

    Article  CAS  Google Scholar 

  11. Zafar, M., Ezzat, S., Ramyar, L., Pan, N., Smyth, H. S., & Asa, S. L. (1995). Cell-specific expression of estrogen receptor in the human pituitary and its adenomas. The Journal of Clinical Endocrinology and Metabolism, 80(12), 3621–3627

    CAS  PubMed  Google Scholar 

  12. Fink, G. (1988). Gonadotropin secretion and its control. In E. Knobil, & J. Neill (Eds.), The Physiology of Reproduction (pp. 1349–1377). New York, United States: Raven Press

    Google Scholar 

  13. Brailoiu, E., Dun, S. L., Brailoiu, G. C., Mizuo, K., Sklar, L. A., Oprea, T. I. … Dun, N. J. (2007). Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system. The Journal of Endocrinology, 193(2), 311–321

    Article  CAS  Google Scholar 

  14. Hazell, G. G., Yao, S. T., Roper, J. A., Prossnitz, E. R., O’Carroll, A. M., & Lolait, S. J. (2009). Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. The Journal of Endocrinology, 202(2), 223–236

    Article  CAS  Google Scholar 

  15. Lebesgue, D., Reyna-Neyra, A., Huang, X., & Etgen, A. M. (2009). GPR30 differentially regulates short latency responses of luteinising hormone and prolactin secretion to oestradiol. Journal of Neuroendocrinology, 21(9), 743–752

    Article  CAS  Google Scholar 

  16. Camilletti, M. A., Abeledo-Machado, A., Ferraris, J., Pérez, P. A., Faraoni, E. Y., Pisera, D. … Díaz-Torga, G. (2019). Role of GPER in the anterior pituitary gland focusing on lactotroph function. The Journal of Endocrinology, 240(2), 99–110

    Article  CAS  Google Scholar 

  17. Hartz, A. M., Madole, E. K., Miller, D. S., & Bauer, B. (2010). Estrogen receptor beta signaling through phosphatase and tensin homolog/phosphoinositide 3-kinase/Akt/glycogen synthase kinase 3 down-regulates blood-brain barrier breast cancer resistance protein. The Journal of Pharmacology and Experimental Therapeutics, 334(2), 467–476

    Article  CAS  Google Scholar 

  18. Huang, B., Butler, R., Miao, Y., Dai, Y., Wu, W., Su, W. … Gustafsson, J. (2016). Å. Dysregulation of Notch and ERα signaling in AhR-/- male mice. Proceedings of the National Academy of Sciences of the United States of America, 113(42), 11883–11888

  19. Kotula-Balak, M., Pawlicki, P., Milon, A., Tworzydlo, W., Sekula, M., Pacwa, A. … Galas, J. (2018). The role of G-protein-coupled membrane estrogen receptor in mouse Leydig cell function-in vivo and in vitro evaluation. Cell and Tissue Research, 374(2), 389–412

    Article  CAS  Google Scholar 

  20. Stauffer, S. R., Coletta, C. J., Tedesco, R., Nishiguchi, G., Carlson, K., Sun, J. … Katzenellenbogen, J. A. (2000). Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. Journal of Medicinal Chemistry, 43(26), 4934–4947

    Article  CAS  Google Scholar 

  21. Bologa, C. G., Revankar, C. M., Young, S. M., Edwards, B. S., Arterburn, J. B., Kiselyov, A. S. … Prossnitz, E. R. (2006). Virtual and biomolecular screening converge on a selective agonist for GPR30. Nature Chemical Biology, 2(4), 207–212

    Article  CAS  Google Scholar 

  22. Meyers, M. J., Sun, J., Carlson, K. E., Marriner, G. A., Katzenellenbogen, B. S., & Katzenellenbogen, J. A. (2001). Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. Journal of Medicinal Chemistry, 44(24), 4230–4251

    Article  CAS  Google Scholar 

  23. Enmark, E., & Gustafsson, J. A. (1999). Oestrogen receptors-an overview. Journal of Internal Medicine, 246(2), 133–138

    Article  CAS  Google Scholar 

  24. Vaillant, C., Chesnel, F., Schausi, D., Tiffoche, C., & Thieulant, M. L. (2002). Expression of estrogen receptor subtypes in rat pituitary gland during pregnancy and lactation. Endocrinology, 143(11), 4249–4258

    Article  CAS  Google Scholar 

  25. Shughrue, P. J., Lane, M. V., Scrimo, P. J., & Merchenthaler, I. (1998). Comparative distribution of estrogen receptor-alpha (ER-alpha) and beta (ER-beta) mRNA in the rat pituitary, gonad, and reproductive tract. Steroids, 63(10), 498–504

    Article  CAS  Google Scholar 

  26. Maurer, R. A. (1982). Estradiol regulates the transcription of the prolactin gene. The Journal of Biological Chemistry, 257(5), 2133–2136

    Article  CAS  Google Scholar 

  27. Couse, J. F., Lindzey, J., Grandien, K., Gustafsson, J. A., & Korach, K. S. (1997). Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse. Endocrinology, 138(11), 4613–4621

    Article  CAS  Google Scholar 

  28. Keefer, D. A., Stumpf, W. E., & Petrusz, P. (1976). Quantitative autoradiographic assessment of 3H-estradiol uptake in immunocytochemically characterized pituitary cells. Cell and Tissue Research, 166(1), 25–35

    Article  CAS  Google Scholar 

  29. Kaya, H., Sezik, M., Ozkaya, O., Dittrich, R., Siebzehnrubl, E., & Wildt, L. (2004). Lipid peroxidation at various estradiol concentrations in human circulation during ovarian stimulation with exogenous gonadotropins. Hormone and metabolic research, 36(10), 693–695

    Article  CAS  Google Scholar 

  30. MacLusky, N. J. (1988). Developmental actions of gonadal steroids. Progress in clinical and biological research, 281, 243–263

    CAS  PubMed  Google Scholar 

  31. Montano, M. M., Welshons, W. V., & vom Saal, F. S. (1995). Free estradiol in serum and brain uptake of estradiol during fetal and neonatal sexual differentiation in female rats. Biology of reproduction, 53(5), 1198–1207

    Article  CAS  Google Scholar 

Download references

Funding

This research was funded by the China Postdoctoral Science Foundation (no. 2019M663101), the Shenzhen San-Ming Project (no. SZSM201612010), and the Shenzhen High-level Hospital Construction Fund.

Author information

Authors and Affiliations

Authors

Contributions

YX and DC conceived and designed the research, performed the experiments, analyzed data, and wrote the manuscript.

Corresponding author

Correspondence to Dong Chen.

Ethics declarations

Ethics Approval

The study was conducted according to the recommended guidelines for the care and use of laboratory animals for research and teaching at Shenzhen University.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, Y., Chen, D. ERα, but not ERβ and GPER, Mediates Estradiol-Induced Secretion of TSH in Mouse Pituitary. Appl Biochem Biotechnol 194, 2492–2502 (2022). https://doi.org/10.1007/s12010-022-03823-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-022-03823-w

Keywords