Covid-19: Men are more likely to have a dysregulated HPA axis associated with depressive symptoms


Depression is a common mental health condition that affects millions of people worldwide. It is characterized by a persistent feeling of sadness or loss of interest in activities that were once enjoyable. Depression is thought to be caused by a complex interplay of genetic, environmental, and psychological factors.

One of the biological factors that may contribute to depression is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a complex hormonal pathway involved in regulating the body’s response to stress. When a person experiences stress, the HPA axis is activated, leading to the release of cortisol, a hormone that helps the body cope with stress. However, chronic activation of the HPA axis can lead to dysregulation, which is thought to contribute to the development of depression.

The hypothalamic-pituitary-adrenal (HPA) axis is a complex hormonal pathway that plays a key role in regulating the body’s response to stress. The HPA axis is made up of three key components: the hypothalamus, the pituitary gland, and the adrenal glands.

The hypothalamus is a small area of the brain that helps regulate many of the body’s basic functions, including temperature, hunger, and thirst. In response to stress, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland.

The pituitary gland, located at the base of the brain, is often referred to as the “master gland” because it produces and releases a wide range of hormones that regulate various bodily functions. In response to CRH from the hypothalamus, the pituitary gland releases adrenocorticotropic hormone (ACTH) into the bloodstream.

ACTH travels to the adrenal glands, which are small, triangular-shaped glands located on top of the kidneys. In response to ACTH, the adrenal glands release cortisol, a hormone that helps the body cope with stress. Cortisol has many effects on the body, including increasing blood sugar levels, suppressing the immune system, and altering metabolism.

The HPA axis is tightly regulated through a series of feedback mechanisms to prevent overactivity or underactivity. For example, when cortisol levels in the blood reach a certain level, they signal the hypothalamus and pituitary gland to stop releasing CRH and ACTH, respectively. This negative feedback loop helps to keep the HPA axis in balance.

However, chronic activation of the HPA axis can lead to dysregulation, which is thought to contribute to the development of various health problems, including depression, anxiety, and cardiovascular disease. Dysregulation of the HPA axis can result in an overactive or underactive stress response, which can lead to a variety of symptoms and health problems.

Overall, the HPA axis is a complex hormonal pathway that plays a key role in regulating the body’s response to stress. Dysregulation of the HPA axis can contribute to various health problems, and understanding the underlying mechanisms of HPA axis dysregulation is an important area of research.

Research studies have found that men may be more likely to have dysregulated HPA axis activity associated with depressive symptoms compared to women. For example, one study found that men with major depression had higher cortisol levels compared to women with major depression, even after controlling for other factors such as age and body mass index (BMI) (Young et al., 2004). Another study found that men with depression had a blunted cortisol response to stress compared to women with depression (Juruena et al., 2006).

These findings suggest that men may be more susceptible to dysregulation of the HPA axis in the context of depression. However, it is important to note that these gender differences are not always consistent across all studies, and more research is needed to better understand the role of the HPA axis in depression and how it may differ between men and women.

Other factors that may contribute to the gender differences in HPA axis dysregulation and depression include differences in genetic and hormonal factors, as well as differences in social and environmental factors such as stress exposure and coping mechanisms

Schematic overview of the hypothalamic-pituitary-adrenal (HPA) axis. Stress activates the secretion into the portal circulation of the corticotropin-releasing hormone (CRH) and other ACTH secretagogues (e.g., vasopressin) then, ACTH stimulates the adrenal glands to synthesize and releases norepinephrine and glucocorticoids, primarily cortisol. Glucocorticoids, in turn, act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle. reference link :

The COVID-19 pandemic has had a significant impact on mental health, with many people experiencing increased levels of stress, anxiety, and depression. One possible explanation for this is that the pandemic may be causing dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, a hormonal pathway that plays a key role in regulating the body’s response to stress.

Research studies have suggested that dysregulation of the HPA axis may be associated with depressive symptoms in people with COVID-19. For example, a study published in the Journal of Psychiatric Research found that patients with COVID-19 who had depressive symptoms had significantly higher levels of cortisol, a hormone that is released in response to stress, compared to patients without depressive symptoms.

Another study published in the journal Brain, Behavior, and Immunity found that COVID-19 patients with higher levels of cortisol and dysregulated cortisol secretion patterns were more likely to develop depression and anxiety symptoms during hospitalization.

In addition to cortisol, dysregulation of other hormones involved in the HPA axis, such as corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), may also contribute to the development of depressive symptoms in people with COVID-19. Research studies have suggested that dysregulated levels of CRH and ACTH may be associated with depressive symptoms in people with COVID-19.

There are several possible mechanisms by which dysregulation of the HPA axis may contribute to the development of depressive symptoms in people with COVID-19. One possibility is that dysregulation of the HPA axis may lead to chronic inflammation, which is known to be associated with depression. COVID-19 infection is associated with increased levels of inflammation in the body, and dysregulation of the HPA axis may exacerbate this inflammatory response.

Another possibility is that dysregulation of the HPA axis may lead to changes in brain structure and function that contribute to the development of depressive symptoms. Research studies have suggested that dysregulation of the HPA axis may be associated with changes in brain regions that are involved in mood regulation, such as the prefrontal cortex and the amygdala.

Overall, dysregulation of the HPA axis may be an important underlying mechanism linking COVID-19 infection and depressive symptoms. Further research is needed to fully understand the complex interplay between the HPA axis, inflammation, brain function, and mood in the context of COVID-19, and to develop effective treatments for people experiencing depression during the pandemic.

A new study …..

Previous studies in rodents have shown that chronic dysregulation of circulating CORT – a condition that also occurs in subsets of human MDD patients – impairs reward processing, but there was little mechanistic insight into how CORT dysregulation impairs reward processing. Further, preclinical literature previously reported effects of CORT on operant responding for rewards only in male rodents, yet humans with MDD are majority female.

Here, we specifically set out to study both male and female mice and to identify mechanisms by which chronic CORT dysregulation might impact dopaminergic transmission, which is known to underlie operant responding for rewards. We found that chronic CORT treatment impairs motivation to attain rewards in operant paradigms in both male and female mice (Fig. 1I, J), but by sex-divergent mechanisms. In females, CORT treatment decreases tissue dopamine content in the dorsomedial striatum (DMS; Fig. 2C).

In males, CORT treatment impairs dopamine transporter (DAT) function in DMS (Figs. 3–5). Despite differing mechanisms, both males and females experienced changes in dopaminergic transmission specifically in DMS, tying dopaminergic function in this striatal subregion to the observed deficits in motivation.

This discovery is consistent with studies showing that DMS dopamine governs goal-directed operant responding for rewards and tying tonic dopamine to motivation [18, 19, 25, 26, 55]. Critically, chronic CORT treatment did not affect dopaminergic transmission in the NAcc, consistent with reports that adrenalectomy and CORT replacement do not affect NAcc extracellular dopamine levels [56].

Our discovery of a latent sex difference in the mechanism by which DMS dopamine transmission is affected by CORT treatment adds to a growing body of literature indicating that males and females can display different underlying mechanisms to achieve similar functional or behavioral outcomes [57, 58]. Therefore, it is important not to assume that a lack of observed sex differences at a high level of analysis precludes sex differences in mechanism. Indeed, we must continue to probe for sex differences at the molecular level if we are to appropriately translate preclinical discoveries into medicines that act at the molecular level.

Based on our results, we speculate that reward processing deficits observed in MDD patients with dysregulated CORT may similarly be due to impaired DMS dopamine transmission, caused by distinct mechanisms in males and females. Our speculation is consistent with recent studies showing that individuals with MDD exhibit decreased DAT expression and tonic dopamine within the dorsal striatum [3, 59].

However, to address the aspect of our hypothesis dealing with sex differences, human data must be analyzed by sex. If the sex-divergent mechanisms by which DMS dopamine transmission is impaired in mice hold true for humans, this would suggest that medications for MDD should be tailored by sex. Further, it may be valuable to distinguish MDD patient populations by phenotyping for CORT dysregulation. Notably, previous failed attempts to translate HPA axis-based therapies from rodent models to humans failed to account for sex differences [39]. They also did not include analyses of CORT status or other aspects of HPA axis function, which could help segregate patient populations most amenable to an HPA axis-focused therapeutic approach.

One caveat of our studies is that the chronic CORT treatment we applied significantly increased total plasma CORT in males only. This finding suggests that CORT elevation drives the behavioral and neurobiological effects observed in males, but it is less clear whether CORT elevation is achieved in females. Free CORT, which crosses the blood-brain barrier, may be increased in females due to lower CBG levels, but this hypothesis is not fully confirmed.

The sex difference in total plasma CORT levels in response to CORT pellet implantation is consistent with an extensive literature demonstrating sex differences in feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, which may be fundamental to consider in a variety of stress studies, not only ours [39, 60]. Further, at least one clinical report associated lower CBG levels with MDD in female patients only, which our CORT treatment model intriguingly recapitulates [61].

Follow-up studies are necessary to understand how CORT dosage affects total and free plasma CORT levels in males and females. The dose-response effects of CORT on behavior are known to follow an ‘inverted U’ wherein levels of CORT that are either too high or too low are problematic [62]. While we focused these studies on understanding the effects of elevated CORT, on the downswing of the inverted U, clinical studies have also found that some individuals with MDD exhibit insufficient CORT levels [63].

Therefore, understanding the dose-response relationship between CORT and dopaminergic system function in males and females is important for understanding the full spectrum of MDD etiology. By testing the effects of a range of CORT doses in males and females, we will better understand potential sex differences (or similarities) in CORT’s effects on dopaminergic system function and behavior.

Our findings inspire two related questions regarding CORT’s effects on females: 1) how does chronic CORT treatment decrease DMS dopamine content in females, and 2) why are females resistant to changes in DAT function? CORT treatment’s lack of effect on DMS DAT function in females is likely not due to an interaction with the estrous cycle, as the estrous cycle modulates dopamine reuptake in the ventral, but not dorsal, striatum [53, 64].

Female resistance to CORT-induced impairments in DAT function could be due to their faster metabolism of CORT [65], which could change how chronic CORT treatment impacts gene expression changes in dopamine neurons (among other cell types) through pharmacodynamic differences in glucocorticoid receptor activation. Future studies are needed to address glucocorticoid receptor occupancy and downstream signaling changes that may underlie the effects of CORT on DAT function in males, and dopamine content in females. Sex differences in feedback inhibition of the HPA axis could also lead to a variety of complex effects.

For example, chronic CORT treatment could lead to sex differences in expression and secretion of corticotropin releasing hormone (CRH), a neuropeptide that mediates HPA axis activity and has been shown to modulate dopaminergic transmission and decrease operant responding for rewards [66,67,68,69,70]. This possibility is supported by previous observations that depressive-like behaviors in females (e.g., immobility in the forced swim test) are less directly dependent on CORT levels than the same behaviors in males [71]. Future studies are necessary to determine if, and how, levels of CRH or other HPA axis-related signaling molecules are affected by CORT pellet implantation in both sexes.

In sum, our studies suggest that impairment of DMS dopaminergic transmission is a key mechanism underlying stress-induced deficits caused by CORT dysregulation. Our studies lay the groundwork for further dissecting the relationship between CORT signaling and dopaminergic circuit function. It will also be interesting to investigate how chronic CORT treatment affects downstream DMS circuit function and corticostriatal plasticity to sustain the effects of chronic CORT treatment [72]. The more we elucidate these pathways, identifying common mechanisms as well as sex differences, the more we will progress towards new therapeutic approaches for stress-related psychiatric disorders such as MDD.

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