Development of the HPA axis: Where and when do sex differences manifest?

doi:10.1016/j.yfrne.2014.03.002

Frontiers in Neuroendocrinology

Volume 35, Issue 3, August 2014, Pages 285-302

https://doi.org/10.1016/j.yfrne.2014.03.002 Get rights and content

Highlights

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Sex differences in stress occur at levels of perception and biochemical response.
•
The HPA axis continues to develop until after puberty.
•
Sex steroids exert profound control over the HPA axis.
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Sex differences in stress responses are mediated both centrally and peripherally.
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Understanding mechanisms of dimorphic stress responses may improve treatment.

Abstract

Sex differences in the response to stress contribute to sex differences in somatic, neurological, and psychiatric diseases. Despite a growing literature on the mechanisms that mediate sex differences in the stress response, the ontogeny of these differences has not been comprehensively reviewed. This review focuses on the development of the hypothalamic–pituitary–adrenal (HPA) axis, a key component of the body’s response to stress, and examines the critical points of divergence during development between males and females. Insight gained from animal models and clinical studies are presented to fully illustrate the current state of knowledge regarding sex differences in response to stress over development. An appreciation for the developmental timelines of the components of the HPA axis will provide a foundation for future areas of study by highlighting both what is known and calling attention to areas in which sex differences in the development of the HPA axis have been understudied.

Graphical abstract

Introduction

The stress response provides the necessary metabolic realignment essential for survival when faced with a challenge (Fig. 1). However, the stress system evolved to respond to physical challenges and the inclusion of modern-day non-physiological chronic stressors has led to the increased manifestation of stress-induced disorders. The increased incidence of stress-induced disorders facilitated the observation of distinct sex differences in stress-induced pathology and has led to the investigation of differences in the types of stressors that males and females respond to behaviorally (Matthews et al., 1991) and the observations that chronic stress induces changes in physiology and behavior (Chrousos and Gold, 1992) for both sexes. The hypothalamic–pituitary–adrenal (HPA) axis mediates a portion of the stress response and is aptly named to describe three of the major structures of the axis. Sex differences in the HPA axis, and the portion of the stress response that it mediates, largely arise during puberty; however, the initial development of the structures of the HPA axis is relevant to the means by which sex differences later manifest. Therefore, this review discusses embryological development of HPA axis components, pubertal changes, and ultimately sex differences in HPA axis function across the lifespan.

Section snippets

Embryology/anatomy

The HPA axis begins at the hypothalamus, which, like the rest of the brain, is derived from the neural tube. The neural tube is the vertebrate embryo’s precursor to the spinal cord and brain structures (Muller and O’Rahilly, 1988, Sadler, 2005). From the open cranial end of the neural tube, the prosencephalic vesicle (ultimately the cerebrum, optic vesicle, and hypothalamus) develops and folds, the caudal fold becomes the diencephalon (Sadler, 2005). The lateral walls of the diencephalon extend

Embryology/anatomy

CRF released from the PVN of the hypothalamus stimulates the release of ACTH from the anterior pituitary. The anterior pituitary derives from a cranial protuberance of the oral ectoderm called “Rathke’s pouch” as early as in the third week of gestation. Rathke’s pouch reaches upwards and comes in close physical contact with the floor of the hypothalamus, called the neuroectoderm, an association which is critical for the differentiation of the anterior pituitary cells into its five secretory

Embryology/anatomy

The sites of action for ACTH within the HPA axis are the adrenal glands, peripheral endocrine organs that are located anterior to the kidneys (Fig. 2). The adreno-gonadal progenitor cells, that eventually give rise to the steroid-forming cells of the adrenal cortex and the gonads, originate from the fetal mesoderm and develop close to the fourth week of gestation. The adreno-gonadal progenitor cells arise between the urogenital ridge and dorsal mesentery as a common group, which within one week

Diurnal rhythms

The HPA axis exhibits a robust circadian rhythm and deficits in the circadian rhythm of the HPA axis have been implicated in disease states (Papanicolaou et al., 1998, Kaneko et al., 1992, Young et al., 2004). The circadian rhythm of the HPA axis is facilitated in large part by the anterior corticotrophs of the pituitary which are able to sustain pulsed secretion of ACTH, even in the absence of CRF, due to intrinsic pulsatility properties (Gambacciani et al., 1987). ACTH is secreted in pulses

Stimulation of the HPA axis

The review to this point has discussed the development, function, and regulation of the three major components of the HPA axis and the related hormones of these regions largely in isolation from one another. In order to fully identify and understand sex differences in the HPA axis it is also necessary to consider the Gestalt condition and collective function the HPA axis.

Conclusions

Sex differences in the HPA axis have been documented as early as the neonatal period, at all individual levels of the HPA axis, as well as in the conglomerate function of the axis. One important point to remember when critically reviewing the existing literature on sex differences in HPA axis function is that demonstration of HPA axis modulation by one sex steroid or another does not make that mechanism sex-specific. This is due to the fact that both males and females produce all sex steroids,

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ReviewDevelopment of the HPA axis: Where and when do sex differences manifest?

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Embryology/anatomy

Embryology/anatomy

Embryology/anatomy

Diurnal rhythms

Stimulation of the HPA axis

Conclusions

Peptides

J. Lipid Res.

Vitam. Horm.

J. Psychiatr. Res.

Brain Res. Mol. Brain Res.

Psychoneuroendocrinology

Horm. Behav.

Psychoneuroendocrinology

Psychoneuroendocrinology

J. Allergy Clin. Immunol.

Recent Prog. Horm. Res.

Biol. Psychiatry

Steroids

Lancet

Trends Endocrinol. Metab.

Physiol. Behav.

J. Steroid Biochem.

Mol. Cell. Endocrinol.

J. Biol. Chem.

J. Biol. Chem.

Prog. Neuropsychopharmacol. Biol. Psychiatry

J. Psychosom. Res.

Horm. Behav.

J. Biol. Chem.

Gen. Comp. Endocrinol.

Genomics

Neurobiol. Dis.

Mol. Cell. Endocrinol.

Prog. Brain Res.

J. Steroid Biochem.

J. Biol. Chem.

Brain Res.

Role of hydrophobic amino acid clusters in the transactivation activity of the human glucocorticoid receptor

Mol. Cell. Biol.

Role of important hydrophobic amino acids in the interaction between the glucocorticoid receptor tau 1-core activation domain and target factors

Biochemistry

Development of the diencephalon in the rat. III. Ontogeny of the specialized ventricular linings of the hypothalamic third ventricle

J. Comp. Neurol.

Development of the diencephalon in the rat. II. Correlation of the embryonic development of the hypothalamus with the time of origin of its neurons

J. Comp. Neurol.

Development of the diencephalon in the rat. I. Autoradiographic study of the time of origin and settling patterns of neurons of the hypothalamus

J Comp Neurol

The development of the rat hypothalamus

Adv. Anat. Embryol. Cell Biol.

Receptors mediating the CRH effects of vasopressin and oxytocin

Ann. N. Y. Acad. Sci.

Stress hormones: their interaction and regulation

Science

Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans

J. Clin. Invest.

Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology

Mol. Psychiatry

A direct androgenic involvement in the expression of human corticotropin-releasing hormone

Mol. Psychiatry

Analysis of FKBP51/FKBP52 chimeras and mutants for Hsp90 binding and association with progesterone receptor complexes

Mol. Endocrinol.

Effects of glucocorticoids and exercise on pancreatic beta-cell function and diabetes development

Diabetes Metab. Res. Rev.

Psychiatric disorder and dysfunction in the UK National Survey of Psychiatric Morbidity

Soc. Psychiatry Psychiatr. Epidemiol.

Cortico-amygdala circuits: role in the conditioned stress response

Stress

Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids

Nature

Cortisol effects on attentional processes in man as indicated by event-related potentials

Psychophysiology

Influences of cortisol on auditory evoked potentials (AEPs) and mood in humans

Neuropsychobiology

Review
Development of the HPA axis: Where and when do sex differences manifest?