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 more likely to experience them.
“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]
The Introduction reports that many neuropsychiatric disorders involve HPA-axis dysregulation and sex differences in risk. It specifically says major depressive disorder is at least twice as common in women and is associated with altered HPA activity. The cited passages do not establish that women are also more likely to experience anxiety disorders. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBasal CORT levels are higher in females than males.
“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]
Section 5.1 reports greater basal adrenal glucocorticoid secretion in female than male rodents, supporting the claim for rodents. It also says the direction of sex differences can depend on species, so the unqualified statement about females and males is broader than the source supports. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFollowing restraint stress, glucocorticoid release is higher in females than males.
“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]
Section 5.1 reports greater stress-induced glucocorticoid secretion in female than male rodents. Section 5.3 discusses corticosterone following restraint stress, but does not give a female–male comparison for that specific stressor. The review also cautions that the direction of the sex difference can depend on species. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOVX females showed reduced CORT release following restraint stress.
“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]
Section 5.3 states that ovariectomy reduces stress-induced CORT secretion in female rodents. It specifically mentions reduced CORT following restraint stress for animals given an estrogen-receptor antagonist, not for ovariectomized females, so the restraint-specific part of the claim is not established. (LLM, conf=0.84)
Experimental — accuracy not yet measuredWhile E2 increases HPA axis reactivity, T reduces HPA axis reactivity.
“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]
Experimental — accuracy not yet measured
ERbeta binds to the promoter of all three neuropeptides.
“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]
Both ER receptors are found throughout the brain and have overlapping expression in numerous areas important in HPA axis regulation.
“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]
T treatment reduced CORT release in response to stressors when administered into brain areas that synapse onto the PVN, and DHT administered just above the PVN also reduced CORT release.
“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]
Through gonadal steroids, the HPG axis can modulate the HPA axis.
“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]
T binds to AR, which is expressed in hypothalamic reproductive areas such as the ARC, VMN and POA nuclei.
“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]
The inconsistency of E2's effect on the HPA axis relates to E2 activity at ERalpha and ERbeta.
“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]
Signaling through ERalpha and ERbeta yields opposing effects on HPA axis reactivity, with ERalpha increasing and ERbeta inhibiting it.
“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]
E2 increases HPA axis reactivity.
“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 effects of E2 on HPA axis reactivity were not always consistent.
“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]
The gender disparity in anxiety and mood disorders supports a role for gonadal steroids E2, P4, and T in modulating the HPA axis.
“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]
Androgens and estrogens provide negative feedback at hypothalamus and pituitary level to suppress LH in men and women, respectively.
“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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- 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
- 493
- 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
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.
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