Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2
Open accessAbstract
Oral estrogen administration attenuates the metabolic action of growth hormone (GH) in humans. To investigate the mechanism involved, we studied the effects of estrogen on GH signaling through Janus kinase (JAK)2 and the signal transducers and activators of transcription (STATs) in HEK293 cells stably expressing the GH receptor (293GHR), HuH7 (hepatoma) and T-47D (breast cancer) cells. 293GHR cells were transiently transfected with an estrogen receptor-alpha expression plasmid and luciferase reporters with binding elements for STAT3 and STAT5 or the beta-casein promoter. GH stimulated the reporter activities by four- to sixfold. Cotreatment with 17beta-estradiol (E(2)) resulted in a dose-dependent reduction in the response of all three reporters to GH to a maximum of 49-66% of control at 100 nM (P < 0.05). No reduction was seen when E(2) was added 1-2 h after GH treatment. Similar inhibitory effects were observed in HuH7 and T-47D cells. E(2) suppressed GH-induced JAK2 phosphorylation, an effect attenuated by actinomycin D, suggesting a requirement for gene expression. Next, we investigated the role of the suppressors of cytokine signaling (SOCS) in E(2) inhibition. E(2) increased the mRNA abundance of SOCS-2 but not SOCS-1 and SOCS-3 in HEK293 cells. The inhibitory effect of E(2) was absent in cells lacking SOCS-2 but not in those lacking SOCS-1 and SOCS-3. In conclusion, estrogen inhibits GH signaling, an action mediated by SOCS-2. This paper provides evidence for regulatory interaction between a sex steroid and the GHJAKSTAT pathway, in which SOCS-2 plays a central mechanistic role.
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The underlying mechanism of oestrogen's effect relates to liver-specific suppression of GH receptor signaling by estrogens stimulating SOCS-2 expression.
“There is strong evidence that the underlying mechanism relates to a liver specific suppression of the GH receptor signaling by estrogens stimulating the expression of proteins (SOCs-2) that inhibit cytokine receptor signaling.”
From The hypothalamus-pituitary-thyroid (HPT)-axis and its role in physiology and pathophysiology of other hypothalamus-pituitary functions (2021) · cites this paper as Leung et al., 2003
Estrogens inhibit GH-dependent, hepatic IGF-1 production, the major pathway of GH action.
“Furthermore, estrogens inhibit GH-dependent, hepatic IGF-1 production, the major pathway of GH action (171, 172).”
From Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance (2018) · cites this paper as [171]
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- Authors
- Leung, K. C., Doyle, N., Ballesteros, M., Sjogren, K., Watts, C. K. W., Low, T. H., Leong, G. M., Ross, R. J. M., & Ho, K. K. Y.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Pituitary Research Unit and Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney NSW 2010, Australia; and Division of Clinical Sciences, Sheffield University, Sheffield S5 7AU, United Kingdom
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2003-01-27
- Volume
- 100
- Issue
- 3
- Pages
- 1016-1021
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC298718
- OpenAlex
- W2044218149
- Cited by
- 218
- References
- 46
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 12 · 2020: 9 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 11 · 2014: 9 · 2013: 13 · 2012: 8
- FWCI
- 10.20
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Funders
- Eli Lilly and Company
- Vincent Fairfax Family Foundation
- U.S. Army
- Eli Lilly Australia
- Medical Research Council
- National Health and Medical Research Council
- Medical Research and Materiel Command
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- estrogen, growth hormone signaling, JAK2 phosphorylation, SOCS2, suppressor of cytokine signaling, STAT3, STAT5, growth hormone receptor, estrogen receptor alpha, estradiol
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Caseins, Cell Line, Dactinomycin, DNA-Binding Proteins, Dose-Response Relationship, Drug, Estradiol, Estrogens, Fibroblasts, Humans, Milk Proteins, Phosphorylation, Plasmids, Precipitin Tests, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Recombinant Proteins, Repressor Proteins, Transcription Factors, Transcription, Genetic, Vanadates, Blotting, Western, Signal Transduction, Trans-Activators, Interleukin-6, Genes, Reporter, Human Growth Hormone, STAT3 Transcription Factor, STAT5 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Janus Kinase 2
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