Cortisol is one of the major stress-response hormones produced by the adrenal glands. Extra cortisol is produced during a stressful situation. This extra cortisol mobilizes energy resources, causing blood sugar levels to increase, and it increases the appetite to help replenish those spent resources.
Cortisol contributes to the regulation of blood pressure and sleep, and it suppresses inflammation. Cortisol levels naturally fluctuate during the day; they are generally the highest in the morning. But when cortisol levels are continuously high, such as occurs with chronic stress, the increased appetite can lead to over-eating and unnecessary weight gain, as well as unhealthy blood glucose levels. DHEA dehydroepiandrosterone is another hormone produced by the adrenal glands.
It is most well recognized as a precursor to the production of sex hormones testosterone, estrogen, progesterone , but DHEA is also produced in larger quantities in response to stress. Evidence suggests that DHEA acts to moderate the stress response. Specifically, the DHEA-to-cortisol ratio has been correlated with tolerance for stress.
An individual who has a higher ratio more DHEA than cortisol seems to experience less negative effects from the same stressors than a person who has a lower ratio less DHEA than cortisol.
In fact, the average concentration of DHEA-S in the bloodstream is about 10, times higher than the most potent estrogen - estradiol typical estradiol levels around 0. Derived from cholesterol, DHEA is produced by the adrenal glands, brain, ovaries and testes, and is a precursor for the major sex steroids estrogen, progesterone, and testosterone. Sometimes called the "anti-aging hormone" or even the "fountain of youth," it is no wonder that supplementation with DHEA to its mid-normal physiologically youthful levels appears to engender a sense of wellbeing and reestablish that "zest for life" [4].
Unfortunately, once DHEA levels begin to wind down, there are no feedback mechanisms to help restore it. As DHEA and downstream metabolites decrease, the brain loses the protective effects of sex steroids and becomes increasingly vulnerable to neurotoxic effects of cortisol and other potentially damaging factors.
The unbalanced relationship between the too high cortisol and not enough DHEA-S is serious enough that it can create potentially harmful conditions for the hippocampus and contribute to neurodegenerative disease pathology.
DHEA replacement therapy can certainly impede the ravages of aging - adequate levels help ramp up the levels of downstream sex steroids, enhance the ability to adapt to stress , increase libido, improve the body fat ratio, and boost the immune system [6]. Consequently, DHEA-S represents a more stable index of adrenocortical activity and stress accumulated over time, whereas DHEA may better reflect the response to acute stressors.
For many years, DHEA has been regarded as inactive and merely a forerunner of androgens and estrogens in the periphery — this observation was based on the inability to detect classical nuclear DHEA receptors observed those for other steroid hormones estrogens — ER, progestogens — PR, androgens — AR, glucocorticoids — GR, mineralocorticoids — MR.
However, more recent evidence sheds the light on DHEA not just as a pro-hormone, but rather an active hormone in its own right. Nowadays, not only DHEA, but DHEA-S as well are recognized for regulating a myriad of biological processes, with a remarkable tropism especially for the central nervous system. Both hormones modulate neurotransmitter synthesis and release, immunity and inflammation, endothelial and cognitive function, and neurogenesis and neuronal survival.
Independent of age, serum levels of DHEA-S appear to be positively correlated with healthier psychological profiles - executive function, working memory, attention, concentration, enjoyment of leisure activities and overall stress-buffering effect [3]. Imbalance in the DHEA pool tends to be associated with distress and psychopathology, such as depression, anxiety, bipolar disorder, eating disorders, PTSD and perceived stress [9] [10] [11].
Moreover, lower DHEA levels go hand-in-hand with the degree in severity of depression [13]. And on the flip-side, too-high levels have been detected in patients with mania [14]. The fascinating thing about neurosteroids is that they work in a slightly different fashion. There is considerable ambiguity regarding whether a DHEA receptor does, in fact, exist. Specifically, these neurosteroids modulate neuronal excitability by directly interacting with neurotransmitter systems, such as dopamine, serotonin, glutamate, and GABA amongst others [15].
Crudely, all of this means that DHEA-S helps keep that fire going — that the excitatory neurons are firing properly, but also that the fire is burning "just right" and is not out of control. For example, both molecules can stimulate dopamine release, a neurotransmitter well-known for being the "pleasure center" of the brain.
However, the paths to raise dopamine are different. DHEA-S uses genomic, slow, long-lasting mechanisms to do so by upregulating tyrosine hydroxylase levels, the enzyme responsible for dopamine production.
DHEA, on the other hand, signals to increase dopamine levels in rapid, intense, short-lived bursts. This association was unaffected by advancing gestational age [ 49 ]. However, other reports showed that stress and anxiety were significantly associated with subjective feelings of distress, but not with increased cortisol levels in late pregnancy [ 50 ].
Such inconsistencies most likely are due to the inclusion in the cited study of depressed patients, while our study included patients with high anxiety levels but not depressed individuals.
It has been shown that high levels of anxiety over the course of pregnancy predicted steeper increases in cortisol trajectories compared to lower levels of pregnancy anxiety.
In addition, DHEA-S has been shown to play a significant role in protection against negative consequences of stress and anxiety-related behaviors, associated to its anti-glucocorticoid effect [ 37 , 39 ]. Moreover, DHEA-S protects against deleterious effects of cortisol, such as excitatory amino acid— and oxidative stress—induced damage, restores cortisol induced decrements in long-term potentiation, regulates programmed cell death, and promotes neurogenesis in the hippocampus [ 36 , 56 ].
The anti-glucocorticoid mechanism of DHEA-S has been related to its capacity to interfere with the nuclear uptake of activated glucocorticoid receptors in the neurons of the hippocampus [ 57 ]. Impaired DHEA-S secretion together with an increase in cortisol levels results in a higher exposure of the glucocorticoid to CNS and the immune system [ 59 ], enhancing an important cytotoxic over the immunomodulatory effects that glucocorticoids exert on target cells [ 60 ].
This high steroid-related ratio was found significantly associated to depression [ 62 ], cognitive disorders [ 63 ] and a reduction in the hippocampal volume [ 63 ]. Worth to note is that anxiety can be measured with different clinimetric instruments, and the two most widely used are the State and trait anxiety inventory STAI and HARS, both of them have a high sensitivity to detect anxiety symptoms; in addition of showing high correlation when measuring anxiety [ 65 ].
Thereby, any person suffering from a psychiatric disorder or under stress will display high scores in both instruments, as both assess anxiety-related symptoms. Therefore, anxiety scores which measure a variety of subjective feelings, autonomic and somatic symptoms, including cognitive functions and behavioral responses, are highly associated with the activation and arousal of the autonomic nervous system that represents one of the main stress regulatory systems, which plays a critical role in modulating the stress responses [ 66 ].
Long-term exposure to chronic stressors leads to a progressive dysfunction of the autonomic nervous system, the sympathetic-adrenal-medullary and HPA networks implicated in stress responses, whose overactivity may lead to the release of excessive stress hormones such as catecholamines and cortisol, among several other bioactive mediators that impinge into the brain, and promote altered changes in neural functions as well as in limbic structures-associated to the emotional responses, as occurs in mood-related disorders, such as anxiety [ 66 ].
Interestingly, related studies showed that high levels of anxiety may induce an abnormal function of the HPA axis [ 67 ]. This study showed that antenatal maternal anxiety measured by STAI displayed a significant positive correlation with high levels of cortisol, supporting the connection between maternal anxiety and HPA axis deregulation. This anti-glucorticoid steroid was shown to decrease the effects induced by hypercortisolism [ 38 , 39 ] Thus, DHEA-S measurements carried out in our study contribute to the understanding of anxiety during pregnancy.
High anxiety and stress during pregnancy have been linked to adverse maternal health outcomes [ 69 ], postpartum depression [ 2 , 4 , 70 ] and long-lasting negative effects in the offspring in the postnatal life [ 71 ]. In line with this, recent studies from our group showed that pregnant women exhibiting high levels of anxiety symptoms and severe depression in the third trimester of pregnancy displayed an increase of different subsets of Th1, Th2, Th17 and Treg-related immune biomarkers [ 72 ].
As anxiety and depression are strongly co-morbid, and it is hard to disentangle the effects of each one, regarding psychosocial and child outcomes [ 12 ]; maternal depression showed a wider effect on different types of child maladjustment than maternal anxiety, which appeared more specific to internalizing difficulties in the child [ 73 ].
Regarding maternal anxiety and biological responses, previous studies showed that high anxiety and maternal stress conditions during the fetus prenatal life may interfere in immune and endocrine systems in the offspring postnatal life [ 3 , 74 ]. Moreover, several pieces of evidence have consistently demonstrated that glucocorticoid receptor function is impaired in anxiety disorders, showing an increase in basal cortisol levels and hyper-responsiveness of the adrenal cortex during psychosocial stress [ 2 , 16 , 75 ].
In addition, maternal anxiety was shown to produce changes in cognitive functions in adolescents [ 79 ] and depressive mood behavior in 14—year-old teenagers [ 80 ]. These data suggest that antenatal maternal anxiety already before birth promotes crucial changes in the neurodevelopmental program in the newborn along the postnatal life [ 12 , 17 , 67 ].
Thus, the finding of high cortisol levels in pregnant women with high anxiety, suggest that such population is highly sensitive to environmental stressors which contributes to the altered changes in the HPA axis reactivity and dopamine systems [ 2 ] which ultimately could lead to high levels of anxious symptoms in vulnerable subjects, as shown herein, in our recruited ANX population.
In addition, other reports showed that prenatal and postpartum low levels of DHEA-S in plasma were found associated with higher postpartum ratings of depression [ 48 ]. Overall, our findings are of clinical relevance, since high levels of cortisol during pregnancy represent a crucial risk factor that contributes to non-optimal pregnancy outcomes [ 17 , 24 ] such as preterm birth, neonates with lower gestational age and birthweight, high neonatal mortality, and pediatric health problems [ 8 , 66 , 68 ].
Our data suggest that biomarkers associated with an abnormal dysfunction of the HPA axis are crucially important in vulnerable pregnant women exhibiting chronic stress and high levels of anxiety symptoms [ 50 , 54 ]. Our data show that patients exhibiting severe anxiety display a significant increase in serum cortisol and a significant decrease in DHEA-S compared with healthy pregnant women. As anxiety and depression are usually comorbid, it is imperative to perform studies to explore further correlations between biological mediators and anxiety symptoms in women at high risk of developing severe depression during mid to late pregnancy.
Several limitations in the present study should be noted. First, we applied the self-reported HDRS and HARS instruments used to evaluate depressive and anxiety symptoms, which have not been extensively used in pregnant women, as compared to other psychological instruments e. Second, blood sampling was performed at a single time at the entry of participants into the study.
Thus, to detect changes in steroid serum concentrations during late pregnancy two specific blood-sampling time-points must have been elected as the optimum in our studied population. Third, we did not evaluate the prevalence of cigarette smoking in recruited participants, an important variable that might have influenced our results. Also, pre-gestational weight could contribute to further information about the relevance of weight gain and BMI associated with the determination of the steroid profile.
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