The Hypothalamic-Pituitary-Adrenal Axis: Development, Programming Actions of Hormones, and Maternal-Fetal Interactions

Overview

Journal Front Behav Neurosci

Specialty Psychology

Date 2021 Feb 1

PMID 33519393

Citations 118

Authors

Julietta A Sheng

Natalie J Bales

Sage A Myers

Anna I Bautista

Mina Roueinfar

Taben M Hale

Robert J Handa

Affiliations

Soon will be listed here.

Abstract

The hypothalamic-pituitary-adrenal axis is a complex system of neuroendocrine pathways and feedback loops that function to maintain physiological homeostasis. Abnormal development of the hypothalamic-pituitary-adrenal (HPA) axis can further result in long-term alterations in neuropeptide and neurotransmitter synthesis in the central nervous system, as well as glucocorticoid hormone synthesis in the periphery. Together, these changes can potentially lead to a disruption in neuroendocrine, behavioral, autonomic, and metabolic functions in adulthood. In this review, we will discuss the regulation of the HPA axis and its development. We will also examine the maternal-fetal hypothalamic-pituitary-adrenal axis and disruption of the normal fetal environment which becomes a major risk factor for many neurodevelopmental pathologies in adulthood, such as major depressive disorder, anxiety, schizophrenia, and others.

Citing Articles

Neuropsychiatric Abnormalities in Metabolic Disturbances: Interplay of Adipokines and Neurotransmission.

Cheon S, Song J Mol Neurobiol. 2025; .

PMID: 40042730 DOI: 10.1007/s12035-025-04797-6.

Chronic Stress and Headaches: The Role of the HPA Axis and Autonomic Nervous System.

Sic A, Bogicevic M, Brezic N, Nemr C, Knezevic N Biomedicines. 2025; 13(2).

PMID: 40002876 PMC: 11852498. DOI: 10.3390/biomedicines13020463.

Modulation of the Neuro-Cancer Connection by Metabolites of Gut Microbiota.

Mafe A, Busselberg D Biomolecules. 2025; 15(2).

PMID: 40001573 PMC: 11853082. DOI: 10.3390/biom15020270.

The Implementation of Infant Anoesis and Adult Autonoesis in the Retrogenesis and Staging System of the Neurocognitive Disorders: A Proposal for a Multidimensional Person-Centered Model.

Pirani A Geriatrics (Basel). 2025; 10(1).

PMID: 39997519 PMC: 11854936. DOI: 10.3390/geriatrics10010020.

Investigating shared risk variants and genetic etiology between Alzheimer's disease and three stress-related psychiatric disorders: a large-scale genome-wide cross-trait analysis.

Dang W, Hao T, Li N, Zhang H, Li Z, Yu H Front Aging. 2025; 6:1488528.

PMID: 39975850 PMC: 11837265. DOI: 10.3389/fragi.2025.1488528.

References

Tamborski S, Mintz E, Caldwell H . Sex Differences in the Embryonic Development of the Central Oxytocin System in Mice. J Neuroendocrinol. 2016; 28(4). DOI: 10.1111/jne.12364. View

Rankin J, Walker J, Windle R, Lightman S, Terry J . Characterizing dynamic interactions between ultradian glucocorticoid rhythmicity and acute stress using the phase response curve. PLoS One. 2012; 7(2):e30978. PMC: 3283588. DOI: 10.1371/journal.pone.0030978. View

Sapolsky R, Romero L, Munck A . How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000; 21(1):55-89. DOI: 10.1210/edrv.21.1.0389. View

Lindsay R, Lindsay R, Waddell B, Seckl J . Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. Diabetologia. 1996; 39(11):1299-305. DOI: 10.1007/s001250050573. View

Low S, Moisan M, Noble J, Edwards C, Seckl J . Glucocorticoids regulate hippocampal 11 beta-hydroxysteroid dehydrogenase activity and gene expression in vivo in the rat. J Neuroendocrinol. 1994; 6(3):285-90. DOI: 10.1111/j.1365-2826.1994.tb00584.x. View

Ishimoto H, Jaffe R . Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr Rev. 2010; 32(3):317-55. PMC: 3365797. DOI: 10.1210/er.2010-0001. View

Harno E, Gali Ramamoorthy T, Coll A, White A . POMC: The Physiological Power of Hormone Processing. Physiol Rev. 2018; 98(4):2381-2430. PMC: 6170974. DOI: 10.1152/physrev.00024.2017. View

Rozeboom A, Akil H, Seasholtz A . Mineralocorticoid receptor overexpression in forebrain decreases anxiety-like behavior and alters the stress response in mice. Proc Natl Acad Sci U S A. 2007; 104(11):4688-93. PMC: 1838662. DOI: 10.1073/pnas.0606067104. View

Gillies G, Linton E, Lowry P . Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature. 1982; 299(5881):355-7. DOI: 10.1038/299355a0. View

10.

Amar A, Weiss M . Pituitary anatomy and physiology. Neurosurg Clin N Am. 2003; 14(1):11-23, v. DOI: 10.1016/s1042-3680(02)00017-7. View

11.

Akselrod S, Gordon D, Ubel F, Shannon D, Berger A, Cohen R . Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science. 1981; 213(4504):220-2. DOI: 10.1126/science.6166045. View

12.

He X, Treacy M, SIMMONS D, Ingraham H, Swanson L, Rosenfeld M . Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature. 1989; 340(6228):35-41. DOI: 10.1038/340035a0. View

13.

Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky P, Meaney M . Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S A. 1998; 95(9):5335-40. PMC: 20261. DOI: 10.1073/pnas.95.9.5335. View

14.

Heck A, Handa R . Androgens Drive Sex Biases in Hypothalamic Corticotropin-Releasing Hormone Gene Expression After Adrenalectomy of Mice. Endocrinology. 2019; 160(7):1757-1770. PMC: 6594463. DOI: 10.1210/en.2019-00238. View

15.

Cunningham Jr E, Bohn M, Sawchenko P . Organization of adrenergic inputs to the paraventricular and supraoptic nuclei of the hypothalamus in the rat. J Comp Neurol. 1990; 292(4):651-67. DOI: 10.1002/cne.902920413. View

16.

Roper J, OCarroll A, Young 3rd W, Lolait S . The vasopressin Avpr1b receptor: molecular and pharmacological studies. Stress. 2010; 14(1):98-115. PMC: 3016603. DOI: 10.3109/10253890.2010.512376. View

17.

ORegan D, Kenyon C, Seckl J, Holmes M . Prenatal dexamethasone 'programmes' hypotension, but stress-induced hypertension in adult offspring. J Endocrinol. 2008; 196(2):343-52. PMC: 2229630. DOI: 10.1677/JOE-07-0327. View

18.

Longcope C . Adrenal and gonadal androgen secretion in normal females. Clin Endocrinol Metab. 1986; 15(2):213-28. DOI: 10.1016/s0300-595x(86)80021-4. View

19.

Figueiredo H, Bruestle A, Bodie B, Dolgas C, Herman J . The medial prefrontal cortex differentially regulates stress-induced c-fos expression in the forebrain depending on type of stressor. Eur J Neurosci. 2003; 18(8):2357-64. DOI: 10.1046/j.1460-9568.2003.02932.x. View

20.

Stroud L, Papandonatos G, Parade S, Salisbury A, Phipps M, Lester B . Prenatal Major Depressive Disorder, Placenta Glucocorticoid and Serotonergic Signaling, and Infant Cortisol Response. Psychosom Med. 2016; 78(9):979-990. PMC: 6541396. DOI: 10.1097/PSY.0000000000000410. View