The DOI matches its Crossref record; 121 of the 122 references it cites were found in a registry or an index.
Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic–pituitary–adrenal axis via estrogen receptor alpha within the hypothalamus
Open accessAbstract
Numerous studies have established a link between individuals with affective disorders and a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, most notably characterized by a reduced sensitivity to glucocorticoid negative (-) feedback. Furthermore there is a sex difference in the etiology of mood disorders with incidence in females being two to three times that of males, an association that may be a result of the influence of estradiol (E2) on HPA axis function. In these studies, we have examined the effect of E2 on glucocorticoid-mediated HPA axis (-) feedback during both the diurnal peak and the stress-induced rise in corticosterone (CORT). Young adult female Sprague-Dawley (SD) rats were ovariectomized (OVX) and 1 week later treated subcutaneous (s.c.) with oil or estradiol benzoate (EB) for 4 days. On the 4th day of treatment, animals were injected with a single dose of dexamethasone (DEX), or vehicle. EB treatment significantly increased the evening elevation in CORT and the stress-induced rise in CORT. In contrast, DEX treatment reduced the diurnal and stress induced rise in CORT and adrenocorticotropic hormone (ACTH), and this reduction was not apparent following co-treatment with EB. To determine a potential site of E2's action, female SD rats were OVX and 1 week later, wax pellets containing E2, the estrogen receptor beta (ERbeta) agonist diarylpropionitrile (DPN), or the estrogen receptor alpha (ERalpha) agonist propylpyrazoletriol (PPT), was implanted bilaterally and dorsal to the paraventricular nucleus of the hypothalamus (PVN). Seven days later, animals were injected s.c. with a single dose of DEX, or vehicle to test for glucocorticoid-dependent (-) feedback. Results show that E2 and PPT increased, while DPN decreased the diurnal peak and stress-induced CORT and ACTH levels as compared to controls. Furthermore, E2 and PPT impaired the ability of DEX to inhibit both the diurnal and the stress-induced rise in CORT and ACTH, whereas DPN had no effect. Neuronal activation was measured by c-fos mRNA expression within the PVN following restraint. E2 and PPT increased c-fos mRNA, and impaired the normal DEX suppression of neuronal activation in the PVN. Taken together, these data indicate that estradiol causes a dysregulation of HPA axis (-) feedback as evidenced by the inability of DEX to suppress diurnal and stress-induced CORT and ACTH secretion. Additionally, the ability of E2 to inhibit glucocorticoid (-) feedback occurs specifically via ERalpha acting at the level of the PVN.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ERα is also expressed in other GABAergic neurons that project into the PVN”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [90]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ER-α occupancy, on the other hand, has an indirect, trans-synaptic activation in the PVN. The peri-PVN region contains ER-α neurons, and their activation can impair glucocorticoid-mediated negative feedback regulation of the HPA axis (71).”
From Higher Circulating Cortisol in the Follicular vs. Luteal Phase of the Menstrual Cycle: A Meta-Analysis (2020) · cites this paper as [71]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Weiser and Handa (2009) showed that treatment with estradiol could inhibit the negative feedback effects of the synthetic glucocorticoid, dexamethasone, likely through effects on or near the PVN (Weiser & Handa, 2009).”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Weiser & Handa, 2009
The cited source says what the claim attributes to it.
In the citing paper
“The opposite was found when pellets with DPN, the ERβ agonist, were placed in the same region.”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Weiser & Handa, 2009
The cited source says what the claim attributes to it.
In the citing paper
“In this work, direct implant of wax pellets containing E2 or the ERα agonist (PPT) proximal to the PVN increased stress-induced and diurnal peak CORT.”
From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Weiser & Handa, 2009
The cited source says what the claim attributes to it.
In the citing paper
“These results suggest that the GR-induced negative feedback of the HPA axis was impaired by ERα on GABAergic neurons in the peri-PVN area90.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [90]
The cited source says what the claim attributes to it.
In the citing paper
“When rats were treated with EB or an ERα agonist near the PVN, glucocorticoid receptor (GR)-mediated suppression of CORT release following acute restraint stress was inhibited, and this inhibition was not seen when animals were treated with an ERβ agonist.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [90]
The cited source says what the claim attributes to it.
In the citing paper
“suggesting that ERα may reduce inhibitory input into the PVN, thereby reducing negative feedback from the glucocorticoids90.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [90]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Kessler, R. C., Chiu, W. T., Demler, O., & Walters, E. E. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.617 · Cited by 12,052
Sapolsky, R. M., Romero, L. M., & Munck, A. U. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.1.0389 · Cited by 7,541
Sapolsky, R. M. (2000) · Endocrine Reviews · doi:10.1210/er.21.1.55 · Cited by 7,533
Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621
Two receptor systems for corticosterone in rat brain: Microdistribution and differential occupation
REUL, J. M. H. M., & KLOET, E. R. D. (1985) · Endocrinology · doi:10.1210/endo-117-6-2505 · Cited by 2,580
Sex differences in HPA axis responses to stress: a review
Kudielka, B. M., & Kirschbaum, C. (2005) · Biological Psychology · doi:10.1016/j.biopsycho.2004.11.009 · Cited by 1,624
The stress system in the human brain in depression and neurodegeneration
Swaab, D. F., Bao, A.-M., & Lucassen, P. J. (2005) · Ageing Research Reviews · doi:10.1016/j.arr.2005.03.003 · Cited by 984
Buckley, T. M., & Schatzberg, A. F. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1056 · Cited by 964
Estradiol and the Developing Brain
McCARTHY, M. M. (2008) · Physiological Reviews · doi:10.1152/physrev.00010.2007 · Cited by 885 · cited 1×
“Estradiol-GABA interactions are also critical for proper development of the brain [for review see; McCarthy, 2008].”
Di, S., Malcher‐Lopes, R., Halmos, K. C., & Tasker, J. G. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-12-04850.2003 · Cited by 820
Research works printed but not linked: 2
- Cullinan, 1998, Evidence for a PVN site of action for gamma aminobutyric acid in the regulatory control of the rat stress axis, Physiologist, 41, 353
- Suzuki, 2001, Sex differences in the hypothalamo–pituitary–adrenal axis: novel roles for androgen and estrogen receptors, Recent Res Dev Endocr, 69
Cited by
Sorted by citations
Items 201–248 of 248
The cortisol awakening response is blunted in healthy women early postpartum
Høgh, S., Lange, E. Ø., Høgsted, E. S., Larsen, K., Hegaard, H. K., Borgsted, C., & Frøkjær, V. G. (2024) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2024.107048 · Cited by 3
Şahin, Z., Aktaş, O., Kalkan, Ö. F., Cüce, G., Alver, A., Şahin, E., Erdem, Ş., Sağlam, N., Görmüş, Z. I. S., & Kutlu, S. (2024) · Journal of Receptors and Signal Transduction · doi:10.1080/10799893.2024.2333470 · Cited by 3
Tao, H., Zhang, Y., Shen, Y., Chen, Q., & Liu, Z. (2025) · Frontiers in Marine Science · doi:10.3389/fmars.2025.1541351 · Cited by 3
Kudo, M., Yamamoto, S., Hiraga, S., & Masuda, T. (2024) · Journal of Neurochemistry · doi:10.1111/jnc.16262 · Cited by 3
Vasyl, R. R., Haran, B., Lahuta, T., Liberzon, I., & Dosenko, V. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149760 · Cited by 2
Dinkelbach, L., Wudy, S. A., Hartmann, M. F., Libuda, L., Föcker, M., Hebebrand, J., Hinney, A., Nöthlings, U., Alexy, U., Grasemann, C., et al. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120867 · Cited by 3
Pregnancy reduces the responsiveness of the pituitary–adrenal axis to dexamethasone
Manojlović‐Stojanoski, M., Nestorović, N. M., Ristić, N., Trifunović, S. L., Ajdžanović, V. Z., Šošić‐Jurjević, B., & Milošević, V. (2011) · Acta Histochemica · doi:10.1016/j.acthis.2011.10.006 · Cited by 2
Jumes, J. J., Jaques, H. D. S., Vecchia, M. F. D., Ferreira, M. O., Orrutéa, J. F. G., Machado, M. G., Mezoni, M. F., da Silva, R. G. S., Almeida, R. F., Rech, D., et al. (2024) · Brazilian Journal of Medical and Biological Research · doi:10.1590/1414-431x2023e13060 · Cited by 2
Effects of the estrous cycle and sex on stress responses in guinea pigs
Nemeth, M., Herrmann, S. M., Wallner, B., & Millesi, E. (2025) · Scientific Reports · doi:10.1038/s41598-025-11101-y · Cited by 2
Snigdha, S., Lau, E., Ademola, J. I., Frost, R., & Patel, P. (2025) · Menopause The Journal of The North American Menopause Society · doi:10.1097/gme.0000000000002608 · Cited by 2
Liu, Y., Bu, J., Wang, J., Zhao, Y., Peng, S., Liu, L., Su, P., Bai, M., Shen, J.-D., Xu, E., et al. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117432 · Cited by 2
Sharawy, N., Hassan, M. I. A., Rashed, L., Shawky, W., & Rateb, M. (2012) · Modern Research in Inflammation · doi:10.4236/mri.2012.11001 · Cited by 2
Neuroendocrine Mechanisms of Depression
Goldstein, J. M., Holsen, L. M., Cherkerzian, S., Misra, M., & Handra, R. J. (2017) · Oxford University Press eBooks · doi:10.1093/med/9780190681425.003.0029 · Cited by 2
Hormesis and brain metabolism in aging and neurodegeneration
Pereira, R. M., Albernaz-Mariano, K. A., Jucá, P. M., Juliano, V. A. L., Sampaio, L. L., & Munhoz, C. D. (2025) · Progress in brain research · doi:10.1016/bs.pbr.2025.05.005 · Cited by 1
Alewel, D. I., Rentschler, K. M., Schladweiler, M. C. J., Miller, C. N., Gavett, S. H., Evansky, P., Grindstaff, R. D., Williams, W. C., & Kodavanti, U. P. (2025) · Toxicological Sciences · doi:10.1093/toxsci/kfaf084 · Cited by 1
de la Rosa, R., Steinmaus, C., Nardone, A., Keller, A., Acevedo, J., Catterina Ferreccio, R., Smith, M. T., & Sillé, F. C. M. (2026) · Environmental Health · doi:10.1186/s12940-026-01304-9 · Cited by 1
Guedes, M. S., & Yildiz, D. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-04990-x · Cited by 3
Xu, Y., Wu, H., Mu, R., Yang, L., Li, Y., & Xian, M. (2026) · Comprehensive physiology · doi:10.1002/cph4.70115 · Cited by 1
Xega, V., Yang, M. H., & Liu, J.-L. (2026) · Sexes · doi:10.3390/sexes7020022 · Cited by 1
Dose-dependent effects of chronic estrogen treatment on anxiety-related behavior in female mice
Hatachi, A., & Tomihara, K. (2011) · Japanese Journal of Animal Psychology · doi:10.2502/janip.61.2.3 · Cited by 2
Melino, S., & Mormone, E. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.745138 · Cited by 1
Stress, Memory, and Hormonal Influence: Considering Ovarian Hormones in Emotional Memory Intrusions
Daly, K. A., Tsytsurina, A., Mitnick, D. M., & Marshall, A. D. (2025) · Women · doi:10.3390/women5030025 · Cited by 1
Csabafi, K. (2014) · SZTE Repository of Dissertations (University of Szeged) · doi:10.14232/phd.2475 · Cited by 1
Influence of Diet on Stress Response and Behavior
Kitraki, E. (2011) · doi:10.1002/9781118083222.ch28
Liu, J. (2013) · UvA-DARE (University of Amsterdam)
Feeding on Phytoestrogens: Implications of Estrogenic Plants for Primate Ecology
Wasserman, M. D. (2011) · eScholarship (California Digital Library)
Chronic Stress and RCAN1 Expression
RHODES, E. L. (2016) · CU Scholar (University of Colorado Boulder)
Green, M. J. (2017) · Brock University Digital Repository (Brock University)
Role of Stress-Associated Signaling in Addiction
Doncheck, E. M., & Mantsch, J. R. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812202-0.00011-7 · Cited by 1
Depression and Heart Failure in Male and Female Rats: Role of Inflammation and Estrogens
Najjar, F. (2019) · uO Research (University of Ottawa) · doi:10.20381/ruor-23854
Nicholson, K. (2019) · The Atrium (University of Guelph)
Zhao, Y.-J., Li, F., Liu, Q.-L., & Li, Y. (2018) · Journal of Gynecological Oncology · doi:10.25107/2689-9396-v2-id1020
Sharma, K. (2020) · Louisiana State University · doi:10.31390/gradschool_dissertations.5408
Sex Differences in Neuroendocrine-Immune Interactions
Cho, M. J., Shaw, G. A., Venkatesan, A., & Neigh, G. N. (2023) · Masterclass in neuroendocrinology · doi:10.1007/978-3-031-21358-8_10
Association of metalloestrogens exposure with depression in women across reproductive lifespan
Ren, J., Wu, W., Li, J., Hu, Q., Zhang, M., Wang, J., Li, X., Li, Y., & Huang, B. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1486402
Effects of gender-affirming hormones on diurnal cortisol concentrations: A prospective study
Morssinkhof, M. W. L., Doyle, D. M., van der Werf, Y. D., den Heijer, M., Heijboer, A. C., Broekman, B. F. P., & Stenvers, D. J. (2025) · Neurobiology of Stress · doi:10.1016/j.ynstr.2025.100741
Endocrine-metabolic effects of kisspeptin in mammals
Pastor, F. M., Santos, B. R., Silva, J. F., Ocarino, N. M., & Serákides, R. (2026) · General and Comparative Endocrinology · doi:10.1016/j.ygcen.2026.114888
Linking combined oral contraceptive use to systemic immune marker profiles: the role of cortisol
Klinger-König, J., van der Auwera, S., Töpfer, P., Ameling, S., Friedrich, N., Völker, U., Völzke, H., Hertel, J., & Grabe, H. J. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1796526
LaChapelle-Sproat, M. V., Anderson, N. S., & LeGates, T. A. (2026) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2026.100757 · Cited by 1
Impacts of menopausal hormone therapy on Alzheimer's disease biomarkers: A systematic review
Rodrigues, A. C., Valério, F. G., Moura, C. B., da Silva, A. M. P., Tudella, G. C. N., Almeida, S. S., Gomes, A. C., Oliveira, C. E. M., Apóstolos‐Pereira, S. L., & Santos, D. H. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261456766
Nathan, V., Shah, I., Conley, D., Lelah, M., & Dosz, E. (2026) · Nutraceuticals · doi:10.3390/nutraceuticals6030043
Chisupa, C. O., & Manchishi, S. M. (2026) · Neuroendocrinology · doi:10.1159/000553326 · Cited by 1
Behavioral and physiological changes during the estrous cycle of socially housed female guinea pigs
Angori, C. R., Kadrić, R. C., Millesi, E., & Nemeth, M. (2026) · Behavioural Processes · doi:10.1016/j.beproc.2026.105408
Tomihara, K., & Okawa, T. (2026) · Behavioural Brain Research · doi:10.1016/j.bbr.2026.116416
Sun, Z., Liu, X., Dong, S., Liu, Q., Wu, K., Zhang, X., Ye, Z., 文薏, Li, M., & Wei, S. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1961915
Metadata
- Authors
- Weiser, M. J., & Handa, R. J.
- Affiliations
- Colorado State University (US)
- Corresponding author
- Handa, R.J.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 159
- Issue
- 2
- Pages
- 883-895
- ISSN
- 0306-4522 (ISSN-L)
- PMC
- PMC5837863
- OpenAlex
- W2057462574
- Cited by
- 250
- References
- 122
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 13 · 2020: 9 · 2019: 16 · 2018: 16 · 2017: 16 · 2016: 17 · 2015: 16 · 2014: 19 · 2013: 18 · 2012: 17
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- U.S. Public Health Service
- National Institute of Neurological Disorders and Stroke (R01NS039951)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- estradiol, glucocorticoid negative feedback, hypothalamic-pituitary-adrenal axis, estrogen receptor alpha, estrogen receptor beta, paraventricular nucleus, corticosterone, ACTH, dexamethasone, Fos expression, ovariectomy, mood disorders
- MeSH terms
- Adrenocorticotropic Hormone, Animals, Circadian Rhythm, Cortodoxone, Dexamethasone, Estradiol, Female, Glucocorticoids, Hypothalamo-Hypophyseal System, Hypothalamus, Nitriles, Ovariectomy, Phenols, Pituitary-Adrenal System, Propionates, Pyrazoles, Radioimmunoassay, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Estrogen Receptor alpha, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
