What makes up the hpa axis

Smith , PhD Sean M. Wylie W. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC.

Abstract Animals respond to stress by activating a wide array of behavioral and physiological responses that are collectively referred to as the stress response. Keywords: stress , corticotropin-releasing factor , adrenocorticotropic hormone , glucocorticoid , hypothalamus , pituitary gland , adrenal gland.

Anatomy of the stress response The anatomical structures that mediate the stress response are found in both the central nervous system and peripheral tissues.

Open in a separate window. Figure 1. Schematic representation of the hypothalamic-pituitary-adrenal HPA axis. In response to stress, CRF is released into hypophysial portal vessels that access the anterior pituitary gland. Circulating ACTH binds to the melanocortin type 2 receptor MC2-R in the adrenal cortex where it stimulates glucocorticoid synthesis and secretion into the systemic circulation.

Glucocorticoids regulate physiological events and inhibit further HPA axis activation red lines through intracellular receptors that are widely distributed throughout the brain and peripheral tissues. IP3, inositol triphosphate; DAG, diacylglycerol. CRF receptors The physiological actions of the CRF family of peptides are mediated through two distinct receptor subtypes belonging to the class B family of G-protein coupled receptors.

Adrenocorticotropic hormone Pro-opiomelanocortin POMC is a prohormone that is highly expressed in the pituitary and the hypothalamus. Glucocorticoids Glucocorticoids, Cortisol in humans and corticosterone in rodents, are a major subclass of steroid hormones that regulate metabolic, cardiovascular, immune, and behavioral processes. Endocrine regulation of the HPA axis Activation of the HPA axis is a tightly controlled process that involves a wide array of neuronal and endocrine systems.

CRF binding proteins Two soluble proteins have been identified that bind the members of the CRF family of peptides with high affinity. Neuronal regulation of the HPA axis Hypophysiotropic neurons in the PVN are innervated by a diverse constellation of afferent projections from multiple brain regions.

Figure 2. Depiction of the major brain regions and neurotransmitter groups that supply afferent innervation to the medial parvocellular zone of the paraventricular nucleus PVN. Cell groups of the lamina terminalis relay information concerning the osmotic composition of blood to the PVN through glutamatergic Glu and angiotensinergic Ang neurons. Limbic structures including the hippocampus, prefrontal cortex, and the amygdala contribute to the regulation of PVN neurons through intermediary neurons of the bed nucleus of the stria terminalis BNST.

PIT, pituitary. The functional neuroanatomy of corticotropin-releasing factor. Gba Found Symp. Brain stem neurons Brain stem catecholaminergic centers play an important role in the regulation of the HPA axis. The lamina terminals A series of interconnected cell groups including the subfornical organ SFO , median preoptic nucleus MePO , and the vascular organ of the lamina terminalis are localized on the rostral border of the third ventricle and make up the lamina terminalis.

Hypothalamus The medial parvocellular subdivision of the PVN receives afferent projections from y-aminobutyric acid GABA -ergic neurons of the hypothalamus. Hypothalamus: feeding centers Hypothalamic centers involved in the regulation of energy homeostasis directly innervate PVN neurons. The limbic system Limbic structures of the f orebrain contribute to the regulation of the HPA axis. Limbic system: hippocampus The hippocampus plays an important role in the terminating HPA axis responses to stress.

Limbic system: prefrontal cortex The prefrontal cortex also regulates HPA responses to stress. Limbic system: amygdala In contrast to the hippocampus and the prefrontal cortex, the amygdala is thought to activate the HPA axis. Sympathetic circuits and the stress response Activation of brain stem noradrenergic neurons and sympathetic andrenomedullary circuits further contribute to the body's response to stressful stimuli. Conclusions Maintenance of homeostasis in the presence of real or perceived challenges requires activation of a complex range of responses involving the endocrine, nervous, and immune systems, collectively known as the stress response.

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Kishimoto T. Dautzenberg FM. Thus, the adrenal medulla is an important component of the ANS and responds very rapidly to stressors, releasing epinephrine and norepinephrine into the bloodstream to affect heart rate, blood pressure, metabolism, and others Vinson et al.

The effects of epinephrine and norepinephrine on various physiological systems are emphasized by changes noted in patients with pheochromocytoma, a catecholamine secreting neuroendocrine tumor of the adrenal chromaffin cells Pacak, Symptoms include sweating, heart palpitations, markedly elevated blood pressure, nausea, tremors, and weight loss Parenti et al.

Histologically, the adrenal cortex is composed of three zones. The outer zona glomerulosa produces aldosterone, which is involved in water and mineral balance through its actions on the kidney and colon Rakova et al.

The intermediate zona fasciculata is the thickest region of the adrenal cortex and synthesizes corticosteroids primarily cortisol in the human, corticosterone in most rodents and androgens. Similarly, the innermost zona reticularis also synthesizes adrenal androgens Longcope, Of note, dehydroepiandrosterone DHEA is the most abundant circulating adrenal androgen in adult humans, whereas these are very low in adult rats and mice Dumontet et al.

The adrenal cortex is derived from mesoderm and is dependent upon several transcription factors such as SF-1 steroidogenic factor-1 and DAX-1 dosage-sensitive sex reversal-adrenal hypoplasia. Deletion of either of these genes results in the absence of adrenocortical development in mice Hammer et al.

These fetal adrenal steroids serve as precursors of maternal placental estrogens. The definitive zone is the major producer of fetal cortisol in response to ACTH stimulation.

By contrast, the developing rodent adrenal is quiescent. It is questionable whether the rodent adrenal contains a fetal adrenal zone per se , although some studies indicate a transient fetal adrenal zone based on the presence of fetal adrenal enhancer elements Zubair et al. While the adult cortex of rodents increases in size from late gestation through puberty, the fetal zone cells disappear gradually and accumulate along the boundary with the adrenal medulla Morohashi and Zubair, However, even after the adult zones are developed, the adrenal gland of the rodent fetus does not yet express aldosterone synthase nor does it respond to stimulation by increasing mineralocorticoid or GC synthesis Ehrhart-Bornstein et al.

It is well established that animals and humans respond to threats to their welfare by activating neurons that control neuroendocrine and autonomic responses. For the HPA axis, the endocrine response is characterized by the secretion of GCs from the adrenal cortex. Circulating GCs act on a variety of tissues to mobilize energy stores, induce lipolysis and proteolysis, potentiate vasoconstriction driven by the ANS, suppress reproduction, and alter stress-related behaviors, to allow homeostasis Papadimitriou and Priftis, By contrast, although some benefits to chronic stress exist, chronic activation of the HPA axis has deleterious effects on immune, cardiovascular, metabolic, and neural functions and may decrease the resilience of neurons and glia to subsequent insults McEwen, ; Jauregui-Huerta et al.

Whether these are direct or indirect effects of glucocorticoids remains to be determined. Figure 1. Chronic stress leads to reduced sensitivity of the negative feedback system that governs the hypothalamic-pituitary-adrenal HPA axis. The loss of this negative feedback system is due to an increased level of circulating glucocorticoids GCs. HPA axis dysregulation results in downstream physiological consequences, increasing risk for immune system dysfunction, mood disorders, metabolic disease, and cardiovascular disease.

The HPA axis is governed by a closed-loop GC-dependent negative feedback system that is essential for the termination of the stress response. For example, adrenalectomy decreases GC secretion, which increases PVN neuropeptide expression and secretion in both basal and stress-induced states Sawchenko, ; Imaki et al. Negative feedback can also act at the level of the PVN, the anterior pituitary, and indirectly via brain regions that project to the PVN Akana et al.

Notably, primary sites of negative feedback differ between endogenous and synthetic GC. Endogenous GCs, such as corticosterone, primarily induce negative feedback at the level of the PVN, while the synthetic GC, dexamethasone DEX , functions as a glucocorticoid receptor GR agonist to inhibit GC release at the level of the anterior pituitary gland Spiga et al. GC-dependent negative feedback has further been shown to rely on the rhythmic release of GC in diurnal and ultradian patterns that are fundamental to the termination of the stress response Sapolsky et al.

In all vertebrates, a peak of circulating corticosterone occurs just before the onset of daily activity. An ultradian variation in GC secretion is composed of the pulsatile release of corticosterone and ACTH that occur in response to differential timing of the stimulus and feedback signals within the HPA axis Walker et al.

In contrast to the circadian rhythm, the ultradian rhythm is not under central regulation of the SCN but is likely generated by a pituitary-adrenal feed-forward—feedback loop under constant CRH infusion. Moreover, when high levels of CRH were infused, the ultradian pattern was disrupted and corticosterone oscillations were dampened, further suggesting a dose-dependent effect of CRH on the patterns of GC secretion Rankin et al. MRs have a greater affinity for corticosterone cortisol in humans; Reul and de Kloet, and consequently, they are predominantly bound during low or basal secretion of corticosteroid Reul and de Kloet, Adrenalectomy increases basal CRH and ACTH levels, suggesting that a decrease in circulating corticosterone removes the negative feedback signal Dallman et al.

Studies using transgenic mice that overexpress forebrain MR show reductions in the corticosterone response to restraint and decreases in anxiety-like behaviors Rozeboom et al. Together, such data suggest that the ratio of MR:GR are as influential as absolute levels for regulating stress-induced HPA axis activity and stress-related behaviors.

In contrast to MR, GR has a lesser affinity for corticosterone and is thought to be the primary target for negative feedback when GC levels are elevated Ruel and de Kloet, GRs remain mostly unoccupied during the basal state but are quickly occupied after a stress-induced increase in circulating GCs Reul and de Kloet, This supports the hypothesis that GR activation the return of HPA activity to baseline following high amplitude secretion of corticosteroids after an acute stressor.

The importance of GR in negative feedback regulation is further demonstrated using a transgenic mouse model. Selective knockout of forebrain GR causes an increase in basal and stress-induced corticosterone levels Kolber and Muglia, , further implicating GC binding sites in the forebrain. In comparison, Wei et al. CRH is abundantly produced in neurons of the PVN as well as other brain areas and is highly conserved between humans, rats, and mice Wamsteeker-Cusulin et al.

It is well-known that stressors can similarly increase crh expression in the PVN and CeA Herman and Tasker, with increases in the primary transcript heterologous nuclear RNA for crh , rising within minutes following the application of a stressor Evans et al.

This is followed by subtler increases in crh mRNA Vazquez et al. Following enhanced cellular activity such as following a kainic acid-induced seizure, crh expression also increases and numerous CRH- ir neurons can be visualized in brain areas that normally express modest levels of CRH, including the HC, BNST, and globus pallidus Foradori et al. Within the PVN, CRH is expressed by both pre-autonomic neurons that project to the brainstem and spinal cord Swanson and Kuypers, , as well as neuroendocrine neurons that project to the median eminence.

The cloning and characterization of the CRH receptor were originally reported by Chen et al. This receptor-bound CRH with high affinity and selectivity and was coupled to adenylate cyclase to increase intracellular cyclic adenosine monophosphate cAMP. CRF-R2 had a different distribution in the brain, being found in subcortical regions, with the greatest expression in the lateral septum and ventromedial n.

Such studies indicate widespread effects of CRH with physiological responses selectively mediated by two different receptors. The POMC gene consists of three exons and two introns. Although AVP has been described as regulating osmotic balance, and OT as a principal hormone for parturition, both neuropeptides are co-expressed in about half of the parvocellular CRH-expressing neurons of the PVN after adrenalectomy Sawchenko et al.

Both are thought to be co-released with CRH Bondy et al. It has also been shown that these neuropeptides modify PVN function in a paracrine fashion through local dendritic release within the PVN Neumann, , the net result being regulatory effects on the PVN that are very different from actions on the adenohypophysis.

In the adenohypophysis, AVP is hypothesized to also arise by collateral projections to the median eminence from magnocellular neurons that target the posterior pituitary, or through vessels from the posterior pituitary that connect to the adenohypophysis. To cope with the physiological changes following a stressor, parvocellular neurons of the PVN integrate neural or hormonal input from a variety of sources leading to a physiologic and metabolic response.

Direct inputs arising from the brainstem are essential to integrating HPA reactions to systemic stressors. The co-expression of alpha 1 and alpha 2 receptors in medial parvocellular CRH neurons Cummings and Seybold, ; Day et al. Alpha 1 adrenergic receptors may be primarily responsible for the stimulatory effects of norepinephrine Cummings and Seybold, ; Kiss and Aguilera, ; Khan et al.

Another circuit that strongly influences HPA responses to stress are projections from the median and dorsal raphe nuclei. Serotonergic fibers to the parvocellular PVN Sawchenko et al. Nonetheless, the BNST represents an important modulating region that is gonadal steroid hormone-sensitive. Thus, reducing the inhibitory tone is an effective mechanism to increase HPA axis activity Swanson and Petrovich, In contrast to the CRH peptide, Crh mRNA is robustly expressed during embryonic days 18 and 19, followed by a reduction on days 20 and In the mouse hypothalamus, CRH expression is detected initially on embryonic day 13, but mimics the same trend as the rat and decreases just before the time of birth embryonic day 17—18 in mice , followed by an increase to adult levels thereafter Schmidt et al.

In rodent studies, immunohistochemistry Whitnall et al. Interestingly, more recently, Tamborski et al. The AVP circuitry also becomes sexually dimorphic with the greater synthesis of AVP in males than females during early postnatal stages for more details, see reviews: Szot and Dorsa, ; Rood and De Vries, ; Rood et al.

Gonadal steroids are crucial hormones in the regulation of the adult HPA axis, resulting in stark differences in responsiveness of the axis between sexes. Studies show that testosterone generally depresses the stress response Viau and Meaney, while estradiol can either enhance or inhibit it Handa et al. ERs are ligand-activated transcription factors that bind to estrogen response elements ERE in gene promoters, thereby providing a link between gonadal hormones and transcriptional responses of the HPA axis McEwen et al.

Estrogens have been shown to augment HPA axis activity and the release of the stress-related secretagogues at several sites due to the broad expression of ERs. Similarly, reports have shown that at the level of the adenohypophysis, estradiol results in a greater response to CRH demonstrated by increased ACTH secretion. Ovariectomy decreases HPA axis stress-responses and these effects can be reversed by replacement of estradiol to females Seale et al.

By contrast, some studies have demonstrated that estradiol decreases HPA axis activity or has no effect Young et al. Treatment with estradiol decreased neuronal activation in the PVN Figueiredo et al. Varying reports of the effects of estradiol on the HPA axis could be explained by differing experimental conditions, such as a dose or duration-dependent effect Figueiredo et al.

Androgens are consistently reported to inhibit HPA axis activation and activity Rosinger et al. Castration of male rodents removes endogenous androgens, increasing stress-induced secretion of ACTH and corticosterone Handa et al.

Further, testosterone or dihydrotestosterone replacement is consistently shown to reverse the inhibitory effects, reducing the ACTH and corticosterone response to an acute stressor, suggesting the inhibitory role of testosterone on the HPA axis Williamson and Viau, The alterations in ACTH and corticosterone were not accompanied by alterations to CRH sensitivity in the pituitary, suggesting a more central-mediated effect of androgens.

Recent studies Seale et al. Notably, the effects of dihydrotestosterone, a potent androgenic metabolite of testosterone, are important in the suppression of the HPA axis and GC secretion following stress. Consistent with a study by Handa et al. Androgens additionally are reported to decrease CRH response to stress in castrated males, indicating indirect action of testosterone on CRH synthesis since ARs are not expressed by hypophysiotropic CRH neurons Bingaman et al.

Thus, although interactions between androgen and estrogen actions can occur at the level of ligand identity, interactions on a molecular level are harder to identify. Recently, Mahfouz et al. Whether this overlap indicates functional interactions at a cellular level in rodents remains to be determined, with the caveat that additional factors may modify these cellular mechanisms in humans. It has been proposed that sex differences arise, in part, due to varying levels of GR and MR and the availability of corticosteroids in the brain.

Corticosteroid-binding globulin CBG , a glycoprotein produced by the liver, binds to circulating corticosterone. CBG enhances corticosteroid stability during transport to target tissues, but it also prevents corticosteroids from binding to GR or MR de Kloet et al. Only free corticosterone can exert physiological effects through its actions on its receptors.

Thus, it is important to make a distinction when comparing total plasma corticosterone levels and available corticosterone. In females, CBG is found at levels that are 2-fold higher than in males, but levels of total corticosterone are also significantly higher.

Therefore, the increased levels of CBG may help buffer the increased amount of total plasma corticosterone, contributing to the lack of a sex difference in free corticosterone levels McCormick et al. Moreover, CBG binds acute stress-induced corticosterone, resulting in a delayed free corticosterone response in comparison to total plasma corticosterone, and implicating CBG as an important buffer for available corticosteroids Qian et al.

The greater levels of CBG in females likely contributes to the increased HPA axis activity when compared to males, whereas, low levels of CBG in males may lead to higher availability of free corticosterone and a more robust negative feedback on the HPA axis Viau and Meaney, ; Tinnikov, The sex differences in adult stress responses may also be programmed by neonatal exposure to gonadal steroids suggesting an organizational effect on the neural circuitry controlling patterns of corticosteroid secretion Seale et al.

The mechanism s by which gonadal steroid hormones act to influence HPA function has not been completely resolved but evidence for androgens and estrogens modulating adrenal Kitay, , pituitary Coyne and Kitay, ; Viau and Meaney, and hypothalamic functions Handa et al. The considerable overlap in gonadal and adrenal steroid hormone receptor expression within the neural circuitry of the PVN supports this as a mechanism Figure 2 ; see review Goel et al.

Figure 2. Relationship of inputs of adrenal and gonadal steroid hormone receptors to the circuitry of the HPA axis. Several brain regions secrete adrenal and gonadal hormones that act on receptors in the peri-PVN and paraventricular nucleus PVN. Much of the expression shows considerable overlap. There are two important periods during development in which a surge of testosterone has been reported to defeminize and masculinize the brain of male rodents: late gestation and shortly after birth Weisz and Ward, Whereas many studies have examined the sexual differentiation of reproductive components of the brain, much less has been published regarding the organizational differentiation of the HPA axis.

Postnatal gonadectomy of male rats has been reported to cause a more female-like HPA axis activity in adulthood, characterized by increased basal and stress-induced corticosterone secretion Patchev et al.

Further, inhibiting the aromatase enzyme to prevent the conversion of testosterone to estradiol in neonatal males, has similar lasting consequences of increased basal and stress-induced corticosterone in adulthood. These results implicate the actions of estradiol, as the result of the aromatization of testosterone in the male on the organization of sex differences in the HPA axis Lucion et al. The organizational actions of perinatal steroids have been further supported by studies examining the pulsatile patterns of corticosterone secretion throughout the day, where males show a lower amplitude and frequency of corticosteroid pulses compared to females Seale et al.

Administration of an AR antagonist in a perinatal male increases the amplitude and frequency of corticosteroid pulses to resemble that of adult females. Moreover, perinatal gonadectomy of males also leads to a female-like pulsatile pattern in adulthood, while a single dose of testosterone following gonadectomy reverses this effect. Moreover, females treated with testosterone within 24 h of birth show a male-like pattern of corticosterone secretion Seale et al. These studies implicate an organizational action of testosterone directly through AR or indirectly through ER, via the aromatization of testosterone to estradiol, on the HPA axis Seale et al.

During pregnancy, the stress response of the fetus is immature and relies heavily on inputs from the maternal and placental systems Gunn et al. During late gestation, the fetus becomes capable of secreting CRH and ACTH in response to maternal stress, resulting in corticosterone production Gunn et al. Basal levels of corticosterone during this time are similar to those of adults Meaney et al. Accompanied by the lower levels of corticosterone, these changes are thought to dampen the HPA axis responses.

Such data suggests an adrenal insensitivity may also play a role in the SHRP, but further mechanisms have not yet been determined. Maternal care, quantified through observations of pup licking and maternal arch-backed nursing, are highly correlated with each other Caldji et al. Dams categorized by levels of maternal care show a causal relationship to epigenetic reprogramming that alters negative feedback sensitivity through changes in DNA methylation and histone modifications Weaver et al.

Several studies suggest this may be related to the transcription factor, nerve growth factor-inducible protein A NGFI-A which binds to a promoter region on exon 1—7 of GR Caldji et al.

Offspring that received low levels of maternal care displayed no change in methylation. These studies support the actions of low maternal care to program increased GR expression and increase feedback sensitivity of adult offspring Liu et al.

Additional studies show decreased corticosterone and ACTH responses to acute stress in adulthood of high maternal care-exposed offspring. A genome analysis of chromosome 18 containing NR3C1 found that varying amounts of maternal care correlated with changes in protocadherin loci McGowan et al.

Reports examining promoter region on exon 1—7 of GR methylation found that upregulation of NGFI-A did not alter stress-induced activation of the promoter region on exon 1—7 of GR transcription or total expression of GR Makino et al.

Consistent with this, Witzmann et al. Thus, while epigenetic reprogramming is altered through maternal care, specific mechanisms in which this occurs are still unclear. Maternal separation during fetal development is another variable that influences HPA axis development and adult patterns of stress-reactivity Boccia and Pederson, Prolonged separation from the dam is associated with a hyperactive HPA axis and increased anxiety- and depressive-like behaviors in adult offspring Liu et al.

In contrast, brief separation increases maternal attentiveness to pups, resulting in better attenuation of the stress-response Boccia and Pederson, Rodent studies have demonstrated that these changes are partially a consequence of alterations in the dopaminergic system since prolonged maternal separation caused decreased dopamine uptake associated with changes in dopamine transporter expression Curley et al.

This is thought to lead to increased stress-induced dopamine activity resulting in a hyperactive HPA axis. Long-term consequences include the altered function of 5-HT receptors and transporters, as well as decreased expression of 5-HT receptor subtypes in the PFC and hypothalamus Ladd et al. These changes correlate with increased anxiety- and depressive-like behaviors, suggesting that a signaling pathway linking the dopaminergic and serotonergic systems with stress responses exists, however, specific mechanisms have yet to be elucidated Zakharova et al.

Paternal influences on the stress axis of adult mice have also been reported. Males exposed to 6 weeks of chronic variable stress before breeding had offspring of both sexes with reduced HPA axis activation to acute restraint in adulthood Rodgers et al. This correlated with gene transcription changes in the PVN and BNST of offspring suggesting the possibility of epigenetic reprogramming through the male lineage.

Studies have also investigated paternal retrieval and grooming effects in offspring. Testosterone levels were decreased in offspring from rats with increased paternal retrieval, as was AVP expression in the BNST, and this correlated with reduced aggressiveness in social interaction tests, such as the resident-intruder test Frazier et al.

Such data suggests an important hormonal link between paternal care, testosterone levels, and aggression. Nonetheless, specific mechanisms of how paternal transmission to the offspring occurs have yet to be elucidated. Puberty is a unique developmental event, influenced largely by the maturation of the hypothalamic-pituitary-gonadal HPG axis, which is responsible for gonadal maturation and adult hormone secretory patterns Ojeda and Urbanski, Some reports also suggest that this represents a second critical period for organizational actions of gonadal hormones that further sculpt the HPA axis into its adult-like characteristics Romeo, ; see review Romeo, for a more thorough analysis of age-dependent changes in the HPA axis.

Importantly, HPA axis reactivity is significantly greater before puberty than after puberty. Rat studies in males show an increased and prolonged stress-responsive release of ACTH and GC prepubertally in comparison to post-pubertal animals Goldman et al.

Similarly, the stress-induced activity of CRH neurons in the prepubertal PVN is greater than that of adults, demonstrating that the prolonged prepubertal pattern of corticosterone and ACTH may be driven by increased hypothalamic CRH synthesis Romeo et al. These findings indicate a blunted GC-dependent negative feedback in prepubertal males Romeo et al.

This observation further indicated that puberty represents a critical period during development that renders the brain more vulnerable to environmental perturbations and increases the risk of HPA-related neuropathologies Romeo and McEwen, The changes in the HPA axis do not appear to be the consequence of pubertal rises in testosterone Romeo, However, because the initial increase of gonadotropin-releasing hormone GnRH secretion and kisspeptin occurs near the onset of puberty, one possibility is that changes in the HPA axis observed across puberty are preprogrammed developmental events that are independent of changes in gonadal hormones Romeo, Some reports further suggest that the pubertal rise in estradiol may also play a role in shaping the adult HPA axis.

Studies in pre-pubertal females show an inhibitory effect of estradiol on stress-induced HPA axis function, while estradiol treatment in post-pubertal females shows a stimulatory effect of estradiol during the acute stress response Evuarherhe et al.

Further, regardless of whether females were ovariectomized before or after puberty, administration of estradiol consistently elevated basal and stress-induced GC secretion, as well as GC pulse amplitude and frequency Evuarherhe et al. Data suggests there is a reversal effect of estradiol on HPA axis function during puberty where estradiol is inhibitory before puberty and stimulatory post-puberty, implying an estradiol-independent mechanism in the development of the HPA axis during puberty in adult females Evuarherhe et al.

A growing body of studies has described fetal risk factors for adult diseases that form the basis for the hypothesis of the Developmental Origins of Health and Disease DOHaD; Sandman et al. The DOHaD postulates that there is a critical period of development where the fetus is most sensitive to certain environmental influences that significantly impact short- and long-term health Harris and Seckl, Such environmental influences include maternal stress, which is a likely correlate of fetal overexposure to GC, implying a common pathway in which environmental insults become linked between mother and fetus Edwards et al.

Commonly, administration of synthetic GCs has been a common clinical treatment for women at risk for preterm labor, to improve survival of the newborn by allowing proper lung maturation Liggins and Howie, ; Crowther et al. Betamethasone or DEX is often used Roberts and Dalziel, in the clinic and they do not appear to differ in efficacy Crowther et al.

Therefore, steroid metabolism is redirected to adrenal androgens, resulting in abnormal masculinization of genital development and behaviors in females. Consequently, dexamethasone is administered to female CAH fetuses to inhibit adrenal androgen production and minimize these effects. Notably, these females represent a population that is exposed to dexamethasone early in gestation, a critical period for fetal development.

More recent studies have begun to elucidate long- and short- term consequences of prenatal exposure to excess GC, causing programming effects in the HPA axis of the fetus that result in dysregulation of important physiological functions in adulthood.

A key player mediating the consequences of maternal elevations of GC from stress is the placenta. During pregnancy, GC concentrations in maternal blood are higher than those of the fetus. Figure 3. Prenatal exposure to excess GCs has short- and long- term effects. As a result, fetal exposure to maternal GCs increases, leading to short term effects, observed immediately at birth into adulthood.

The short- and long- term effects on the fetus of maternal elevations of GC due to prenatal stress or prenatal exposure to synthetic GC have been found to depend on the length of exposure and time during development at which the insult occurs Barbazanges et al.

Fujioka et al. However, brief prenatal stress did not cause a change in CRH-expressing PVN neurons, suggesting that the duration of the stressor is important for impacting the normal development of PVN neurons Fujioka et al.

Other studies have investigated the time-dependent effects of fetal exposure to excess GC. Increased peaks and prolonged secretion of these hormones in response to stressors have also been observed Muneoka et al. In contrast, Kamphuis et al. This raises the possibility that the HPA axis can retain sufficient plasticity postnatally to allow reversal of maternal HPA axis hyperactivity in the offspring. Offspring of rodent dams prenatally treated with GC during late gestation typically exhibit reduced birth weights that were consistently reduced throughout life compared to control offspring Carbone et al.

Carbone et al. This was thought to be linked to a dysregulation in growth hormone signaling, thereby reducing transcription of the Igf-1 gene Carbone et al. Together, such data suggest a sex-specific mechanism in which prenatal GC exposure causes a reduction in Ghrh to decrease circulating GH, resulting in lower plasma IGF-1, and reduced birth weights. Evidence for molecular mechanisms underlying these events remains to be determined.

It is well-established that prenatal insults can impact the autonomic system in adult offspring exposed to fetal GC. Angiotensinogen is an important component of the renin-angiotensin-system RAS that is upregulated by GCs Tamura et al. Moreover, adult female offspring exposed to prenatal stress display a more prolonged increase in systolic blood pressure and a longer recovery period when subjected to restraint stress than males Igosheva et al.

Such data are consistent with recent observations of altered R-R interval variability Heart rate variability; HRV in adult offspring exposed to elevated fetal GCs. Adult female, but not male offspring of prenatal GC treated dams exhibit a reduction in high-frequency power when compared to control Madhavpeddi et al. Because high-frequency power represents parasympathetic activity Akselrod et al. Whether this is the same as the responses of prenatal stress remains to be determined but implicate sex-specific programming effects of the ANS due to excess prenatal GC exposure.

In addition to alterations in ANS and neuroendocrine function in adult offspring exposed to elevated GC levels in development, the risk for adult metabolic dysfunction is also increased. Female rats prenatally exposed to high levels of GCs are hyperinsulinemic after oral glucose administration, with alterations in the expression of genes that mediate GC and lipid metabolism in subcutaneous fat Brunton et al.

By contrast, prenatal GC exposure was found to cause hyperglycemia following oral glucose in male offspring Nyirenda et al. These observations suggest sex-specific mechanisms where fetal exposure to GCs programs the stress response, leading to a dysregulation of glucose-insulin homeostasis Brunton et al. These observations suggest a mechanism in which fetal GCs affect important genes in fatty acid metabolism and increase the risk for hepatic steatosis in adulthood Carbone et al.

The developmental origins of the disease model posit that events during fetal and early-life correlate with long-term consequences that encompass the development of neuroendocrine signaling and ultimately susceptibility to neuropsychological and neuropathological diseases in adulthood.

Improper development of the HPA axis is commonly suggested as the primary neuroendocrine system affected by alterations in the prenatal environment. Placental hormones and cytokines are thought to regulate the effects of maternal stress on the fetal HPA axis, but it is important to consider the nature and timing of prenatal insults, as evidence suggests exposure to prenatal stress during various gestational periods and varying lengths of time exerts different effects on HPA axis activity Sandman et al.

However, precise mechanisms in which prenatal stressors influence neuroendocrine signaling between the maternal-placental-fetal interface are still unclear. In humans, a potential prospect is placental CRH, which is upregulated by maternal and fetal cortisol. Thus, sex should be considered more of a leisure activity and not something you become preoccupied with when, for example, you are running from an axe-wielding murderer. While proper functioning of the HPA axis is essential for dealing with stress, when the HPA axis is stimulated too much for example in someone who faces extreme stress on a daily basis , it can lead to physical and psychiatric problems.

Individuals with elevated cortisol levels may experience a suppressed immune system response , making them more susceptible to infection. Repeated HPA axis activation has been linked to type 2 diabetes, obesity, and cardiovascular disease. Cortisol has also been demonstrated to have detrimental effects on memory and cognition, and high cortisol levels are implicated in mood disorders like depression.

Additionally, baseline activity of the HPA axis can be affected by early life experiences, and some studies suggest that early-life trauma may lead to an over-reactive HPA axis later in life. This may contribute to increased anxiety and potential metabolic effects, including excess fat deposition and insulin resistance.

Thus, proper functioning of the HPA axis is crucial in helping us to deal with stressors, but repeated stress has the potential to disrupt the beneficial physiological role of the HPA axis.

Because of its integral role in a healthy response to stress, and the disease that can result when that response is disrupted, the HPA axis is an important area to understand and represents a potential target for therapeutic drugs. Chrousos GP. In humans, the primary GC produced is cortisol, while in rats the primary GC is coricosterone.

Glucocoritoids travel throughout the body including the brain and bind to two nuclear receptor hormones - glucocorticoid receptor GR and mineralocorticoid receptor MR. In the brain, GCs participate in a negative feedback loop meaning that they control their own production by binding to GR and MR in the hypothalamus. Improper functioning and control of the HPA axis have been linked to immune-related diseases like rheumatoid arthritis and asthma exacerbation , decreased metabolic functioning associated with obesity and Cushing syndrome , and mood disorders such as major depression and anxiety disorders.

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