Cited by 250Stress Responses and CortisolEstrogen and related hormone effectsAdrenal Hormones and Disorders

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Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic–pituitary–adrenal axis via estrogen receptor alpha within the hypothalamus

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Weiser, M.J., Handa, R.J.·2009·Neuroscience

DOI 10.1016/j.neuroscience.2008.12.058PMC PMC5837863

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Abstract

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.

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Authors: Weiser, M. J., & Handa, R. J.
Affiliations: Colorado State University (US)
Corresponding author: Handa, R.J.
ORCID: Weiser, M.J.
Handa, R.J.
Venue: Neuroscience
Publisher: Elsevier BV
Published: 2009-03
Volume: 159
Issue: 2
Pages: 883-895
ISSN: 0306-4522 (ISSN-L)
DOI: 10.1016/j.neuroscience.2008.12.058
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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

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Estrogen impairs glucocorticoid dependent negative feedback on the hypothalamic–pituitary–adrenal axis via estrogen receptor alpha within the hypothalamus

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