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

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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  • ERalpha is expressed in other GABAergic neurons that project into the PVN.

    “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]

    The Results section reports ERα in GAD67-positive GABAergic neurons surrounding the PVN, and the Discussion identifies ERα in regions that provide inhibitory GABA input to the PVN. However, the Discussion explicitly says the authors do not know whether the ERα-expressing peri-PVN neurons project directly to the PVN, so the claim is stronger than the evidence for those neurons. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • ER-α occupancy has an indirect, trans-synaptic activation in the PVN and can impair glucocorticoid-mediated negative feedback regulation of the HPA axis.

    “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]

    The Discussion reports that peri-PVN ERα activation increases PVN neuronal activation and impairs dexamethasone suppression of the HPA axis. It proposes an indirect mechanism, but explicitly says direct projections from the relevant peri-PVN neurons to the PVN are unknown; the trans-synaptic mechanism is therefore not established. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Estradiol treatment inhibits the negative feedback effects of dexamethasone, likely through effects on or near the PVN.

    “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

  • Direct implant of ERβ agonist DPN proximal to the PVN decreases stress-induced and diurnal peak CORT.

    “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

  • Direct implant of E2 or ERα agonist PPT proximal to the PVN increases stress-induced and diurnal peak CORT.

    “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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Authors
Weiser, M. J., & Handa, R. J.
Affiliations
Colorado State University (US)
Corresponding author
Handa, R.J.
ORCID
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
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 › Genetics › 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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