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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.
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“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]
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“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]
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“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
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“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
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“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
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“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]
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“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]
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“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]
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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
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Stress and the brain: from adaptation to disease
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Estradiol and the Developing Brain
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Sex differences and stress across the lifespan
Bale, T. L., & Epperson, C. N. (2015) · Nature Neuroscience · doi:10.1038/nn.4112 · Cited by 751
Sex differences in stress-related psychiatric disorders: neurobiological perspectives
Bangasser, D. A., & Valentino, R. J. (2014) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2014.03.008 · Cited by 737
Oyola, M. G., & Handa, R. J. (2017) · Stress · doi:10.1080/10253890.2017.1369523 · Cited by 710
“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).”
BackgroundSelf-citationHeck, A., & Handa, R. J. (2018) · Neuropsychopharmacology · doi:10.1038/s41386-018-0167-9 · Cited by 567
Self-citationSheng, J. A., Bales, N. J., Myers, S. A., Bautista, A. I., Roueinfar, M., Hale, T. M., & Handa, R. J. (2021) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.601939 · Cited by 418
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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
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