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Gonadal steroid hormones and the hypothalamo–pituitary–adrenal axis
Open accessAbstract
The hypothalamo-pituitary-adrenal (HPA) axis represents a complex neuroendocrine feedback loop controlling the secretion of adrenal glucocorticoid hormones. Central to its function is the paraventricular nucleus of the hypothalamus (PVN) where neurons expressing corticotropin releasing factor reside. These HPA motor neurons are a primary site of integration leading to graded endocrine responses to physical and psychological stressors. An important regulatory factor that must be considered, prior to generating an appropriate response is the animal's reproductive status. Thus, PVN neurons express androgen and estrogen receptors and receive input from sites that also express these receptors. Consequently, changes in reproduction and gonadal steroid levels modulate the stress response and this underlies sex differences in HPA axis function. This review examines the make up of the HPA axis and hypothalamo-pituitary-gonadal (HPG) axis and the interactions between the two that should be considered when exploring normal and pathological responses to environmental stressors.
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“Anxiety and mood disorders are associated with HPA axis dysregulation and show large gender disparities, with women being more likely to experience these disorders86.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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
“Numerous studies find that basal CORT levels are higher in females than males”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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.
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“and that following restraint stress, glucocorticoid release was higher in females86”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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.
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“Additionally, OVX females showed reduced levels of CORT release following restraint stress86”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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“While E2 increases HPA axis reactivity, T has been found to reduce HPA axis reactivity86.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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“Additionally, ERβ has been shown to bind to the promoter of all three neuropeptides86.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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“Both ER receptors are found throughout the brain and with overlapping expression in numerous areas important in HPA axis regulation86.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“T treatment reduced CORT release in response to stressors when administered into brain areas that synapse onto the PVN86 as well as when DHT was administered just above the PVN88.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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“Through these gonadal steroids, the HPG axis can exert a modulatory effect over the HPA axis (for review see 63,86).”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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“T binds to AR, which is expressed in hypothalamic reproductive areas, such as the ARC, VMN and POA nuclei86.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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“This inconsistency of E2’s effect on the HPA axis relates to E2 activity at ERα and ERβ.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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“Signaling through these 2 receptors yield opposing effects on HPA axis reactivity, with ERα increasing and ERβ inhibiting HPA axis reactivity (vide infra).”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“suggesting that E2 increases HPA axis reactivity.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
The cited source says what the claim attributes to it.
In the citing paper
“While these data suggest that E2 increases HPA axis reactivity, the effects of E2 were not always consistent86.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
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In the citing paper
“This gender disparity in prevalence supports a role for gonadal steroids, E2, P4, and T, in modulating the HPA axis.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [86]
In the citing paper
“Androgens and estrogens provide negative feedback at the hypothalamus and pituitary level to suppress LH in men and women, respectively [23].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [23]
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Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450
“Androgens and estrogens provide negative feedback at the hypothalamus and pituitary level to suppress LH in men and women, respectively [23].”
Sheng, 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
Self-citation
Metadata
- Authors
- Handa, R. J., & Weiser, M. J.
- Affiliations
- University of Arizona College of Medicine- Phoenix (US)
- Corresponding author
- Handa, Robert J.
- Venue
- Frontiers in Neuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 35
- Issue
- 2
- Pages
- 197-220
- ISSN
- 0091-3022 (ISSN-L)
- PMC
- PMC5802971
- OpenAlex
- W2071721757
- Cited by
- 408
- References
- 492
- Citations by year
- 2026: 22 · 2025: 31 · 2024: 32 · 2023: 24 · 2022: 33 · 2021: 40 · 2020: 27 · 2019: 40 · 2018: 37 · 2017: 35 · 2016: 34 · 2015: 34 · 2014: 19
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Frontiers in Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS039951)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis, sex steroids, paraventricular nucleus, corticotropin-releasing factor, androgen receptor, estrogen receptor, stress response, sex differences, glucocorticoids, reproductive status
- MeSH terms
- Animals, Corticotropin-Releasing Hormone, Humans, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System, Receptors, Estrogen, Gonadal Steroid Hormones, Stress, Physiological
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