The DOI matches its Crossref record; 492 of the 492 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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.
In the citing paper
“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.
In the citing paper
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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 cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Sapolsky, R. M., Romero, L. M., & Munck, A. U. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.1.0389 · Cited by 7,541
Sapolsky, R. M. (2000) · Endocrine Reviews · doi:10.1210/er.21.1.55 · Cited by 7,533
The Steroid and Thyroid Hormone Receptor Superfamily
Evans, R. M. (1988) · Science · doi:10.1126/science.3283939 · Cited by 7,394
The nuclear receptor superfamily: the second decade
Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schütz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90199-x · Cited by 6,964
Protective and Damaging Effects of Stress Mediators
McEwen, B. S. (1998) · New England Journal of Medicine · doi:10.1056/nejm199801153380307 · Cited by 6,733 · cited 1×
“Indeed, chronic activation of the HPA axis results in deleterious effects on immune, cardiovascular, metabolic and neural functions and may decrease the viability of neurons and glia to subsequent neurotoxic insults (JaureguiHuerta et al., 2010; McEwen, 1998; Rajkowska and Miguel-Hidalgo, 2007).”
BackgroundCloning of a novel receptor expressed in rat prostate and ovary.
Kuiper, G. G. J. M., Enmark, E., Pelto‐Huikko, M., Nilsson, S., & Gustafsson, J.-Α. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.12.5925 · Cited by 4,802
Depression: a new animal model sensitive to antidepressant treatments
PORSOLT, R. D., LE PICHON, M., & JALFRE, M. (1977) · Nature · doi:10.1038/266730a0 · Cited by 4,451
Kuiper, G. G. J. M., Carlsson, B., Grandien, K., Enmark, E., Häggblad, J., Nilsson, S., & Gustafsson, J.-A. (1997) · Endocrinology · doi:10.1210/endo.138.3.4979 · Cited by 4,442
Vale, W., Spiess, J., Rivier, C., & Rivier, J. (1981) · Science · doi:10.1126/science.6267699 · Cited by 3,965
Vale, W., Spiess, J., RIVIER, C. L., & Rivier, J. (1982) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-198205000-00013 · Cited by 3,904
Research works printed but not linked: 3
- Bargmann, 1949, Uber die neurosekretorische verknupfung von hypothlamus und neurohypophyse, Z. Zellforsch. Mikrosk. Anat., 34, 610
- Brinton, 1988, Regional distinctions in the regulation of type I and type II adrenal steroid receptors in the central nervous system, Neurosci. Res. Commun., 2, 37
- Safe, 2008, Nonclassical genomic ER/Sp and ER/AP-1 signaling pathways, J. Mol. Endocrinol.
Cited by
Sorted by citations
Sex Differences in Animal Models: Focus on Addiction
Becker, J. B., & Koob, G. F. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011163 · Cited by 725
Cortisol stress reactivity across psychiatric disorders: a systematic review and meta-analysis
Zorn, J. V., Schür, R. R., Boks, M. P., Kahn, R. S., Joëls, M., & Vinkers, C. H. (2017) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2016.11.036 · Cited by 697
Browning, K. N., & Travagli, R. A. (2014) · Comprehensive Physiology · doi:10.1002/cphy.c130055 · Cited by 541
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-citationPruessner, M., Cullen, A. E., Aas, M., & Walker, E. F. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.12.013 · Cited by 315
Acevedo‐Rodriguez, A., Kauffman, A. S., Cherrington, B. D., Borges, C. S., Roepke, T. A., & Laconi, M. (2018) · Journal of neuroendocrinology · doi:10.1111/jne.12590 · Cited by 298
Spiga, F., Walker, J. J., Terry, J. R., & Lightman, S. L. (2014) · Comprehensive Physiology · doi:10.1002/cphy.c140003 · Cited by 267
Burke, A. R., McCormick, C. M., Pellis, S. M., & Lukkes, J. L. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.01.018 · Cited by 225
Panossian, A., Seo, E.-J., & Efferth, T. (2018) · Phytomedicine · doi:10.1016/j.phymed.2018.09.204 · Cited by 127
Sze, Y., & Brunton, P. J. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14615 · Cited by 85
An Integrative Approach to HPA Axis Dysfunction: From Recognition to Recovery
Ring, M. (2025) · The American Journal of Medicine · doi:10.1016/j.amjmed.2025.05.044 · Cited by 89
Goldstein, J. M., Cohen, J. E., Mareckova, K., Holsen, L., Whitfield-Gabrieli, S., Gilman, S. E., Buka, S. L., & Hornig, M. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2014464118 · Cited by 70
Oyola, M. G., Thompson, M. K., Handa, A. Z., & Handa, R. J. (2017) · Journal of Comparative Neurology · doi:10.1002/cne.24295 · Cited by 53
Self-citationCoping with Stress During Aging: The Importance of a Resilient Brain
Sampedro-Piquero, P., Alvarez-Suarez, P., & Begega, A. (2018) · Current Neuropharmacology · doi:10.2174/1570159x15666170915141610 · Cited by 41
Greenberg, G. D., Steinman, M. Q., Doig, I. E., Hao, R., & Trainor, B. C. (2015) · European Journal of Neuroscience · doi:10.1111/ejn.13099 · Cited by 49
Oral contraceptives positively affect mood in healthy PMS-free women: A longitudinal study
Hamstra, D. A., de Kloet, E. R., de Rover, M., & Van der Does, W. (2017) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2017.10.011 · Cited by 41
Brown, G. R., Kulbarsh, K. D., Spencer, K. A., & Duval, C. (2015) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.07.003 · Cited by 33
Cortisol awakening response and testosterone jointly affect adolescents' theory of mind
Wang, H., Zhang, S., Wu, S., Qin, S., & Liu, C. (2022) · Hormones and Behavior · doi:10.1016/j.yhbeh.2022.105258 · Cited by 7
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
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
