No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Tsigos C, Chrousos GPHypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865-871
Abstract
The stress system coordinates the adaptive responses of the organism to stressors of any kind.(1). The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them. CRH plays an important role in inhibiting GnRH secretion during stress, while, via somatostatin, it also inhibits GH, TRH and TSH secretion, suppressing, thus, the reproductive, growth and thyroid functions. Interestingly, all three of these functions receive and depend on positive catecholaminergic input. The end-hormones of the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, on the other hand, have multiple roles. They simultaneously inhibit the CRH, LC/NE and beta-endorphin systems and stimulate the mesocorticolimbic dopaminergic system and the CRH peptidergic central nucleus of the amygdala. In addition, they directly inhibit pituitary gonadotropin, GH and TSH secretion, render the target tissues of sex steroids and growth factors resistant to these substances and suppress the 5' deiodinase, which converts the relatively inactive tetraiodothyronine (T(4)) to triiodothyronine (T(3)), contributing further to the suppression of reproductive, growth and thyroid functions. They also have direct as well as insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension (metabolic syndrome X) and direct effects on the bone, causing "low turnover" osteoporosis. Central CRH, via glucocorticoids and catecholamines, inhibits the inflammatory reaction, while directly secreted by peripheral nerves CRH stimulates local inflammation (immune CRH). CRH antagonists may be useful in human pathologic states, such as melancholic depression and chronic anxiety, associated with chronic hyperactivity of the stress system, along with predictable behavioral, neuroendocrine, metabolic and immune changes, based on the interrelations outlined above. Conversely, potentiators of CRH secretion/action may be useful to treat atypical depression, postpartum depression and the fibromyalgia/chronic fatigue syndromes, all characterized by low HPA axis and LC/NE activity, fatigue, depressive symptomatology, hyperalgesia and increased immune/inflammatory responses to stimuli.
... Гіпоталамус відіграє вирішальну роль в індукуванні гормональних реакцій на стресові подразники через вісь «гіпоталамус -гіпофіз -надниркові залози». Пов'язаний з префронтальною корою та лімбічними структурами, особливо з мигдалеподібним тілом і гіпокампом, гіпоталамус діє як центральний вузол, що інтегрує фізіологічні аспекти реакції на стрес [17]. Відповідно функції гіпоталамуса стосуються патофізіології посттравматичного стресового розладу. ...
... Одночасно з генетичною схильністю і факторами навколишнього середовища посттравматичний стресовий розлад може впливати на психологічний і нейробіологічний стан людей. Під час гострого стресу активується гіпоталамус, який секретує кортикотропін-рилізинг-гормон під впливом серотоніну з мигдалеподібного тіла [17,19]. Після цього кортикотропінрилізинг-гормон стимулює гіпофіз до вивільнення адренокортикотропного гормону, який, у свою чергу, змушує кору надниркових залоз продукувати кортизол, вплив якого може блокувати численні імунні реакції, нейрональні захисні й метаболічні механізми. ...
... Крім того, у низці сучасних досліджень щодо впливу стресу на здоров'я людини показано зв'язок між співвідношенням кортизолу/ДГЕА і розвитком порушень у діяльності серцево-судинної, нервової та репродуктивної систем, а також соціальної адаптації (табл. 1) [17,22]. ...
The modern hostilities have created the unique challenges for medical, surgical and rehabilitation assistance to people liable for military service who have sustained injuries in the battle conditions. The experience of providing medical care for participants of modern military operations has shown that endocrine dysfunction is a leading pathogenetic link that affects the human body in combat surgical trauma and post-traumatic stress disorders. The main pathogenetic mechanism of trauma and post-traumatic stress disorders is associated with dysfunction of the hypothalamic-pituitary-adrenal axis. Hormones such as cortisol, dehydroepiandrosterone, adrenaline and noradrenaline are involved in the neuroendocrine mechanisms of stress development. These hormones regulate and control the stress response, reflecting the stages of its course and the adaptive capacities of the organism. Dysfunction of the hypothalamic-pituitary-thyroid axis has a significant importance in the regulation of both acute and chronic stress accompanied by the clinical development of various thyroid disorders such as hyperthyroidism, Graves’ disease, autoimmune thyroidopathies and nodular transformation. Therefore, the practical significance lies in the clinical studying the key indicators of pituitary-adrenal and pituitary-thyroid function, monitoring the function of the adrenal glands and the thyroid. Correction of these disorders, the treatment and rehabilitation of patients with combat-related traumatic injuries should be carried out with specialized endocrinological assistance. This approach will be relevant for military medicine in Ukraine in the following years.
... The CNS collects from the external (via sensory organs) and internal environment information necessary for the maintenance of homeostasis; it gives significance to this information in terms of danger or threat, as related to personal expectations, past experience and opportunities for control, finally, it initiates the adaptive responses, including behavioural adjustments and neuroendocrine changes to meet the energy requirements for the behavioural response and to maintain homeostasis (Mormede, 2000). Tsigos and Chrousos (2002) reported that activation of the stress system leads to behavioural and peripheral changes. The performance of highly repetitive behaviours has been shown to help animals cope with environment containing little or unvaried stimulation (Friend, 1991). ...
... The performance of highly repetitive behaviours has been shown to help animals cope with environment containing little or unvaried stimulation (Friend, 1991). According to Tsigos and Chrousos (2002), these behavioural and peripheral changes improve the ability of an animal to adjust homeostasis and increase it chances to survive. Tsigos and Chrousos (2002), further reported that the stress system coordinates the adaptive response of the animal to stressors of any kind. ...
... According to Tsigos and Chrousos (2002), these behavioural and peripheral changes improve the ability of an animal to adjust homeostasis and increase it chances to survive. Tsigos and Chrousos (2002), further reported that the stress system coordinates the adaptive response of the animal to stressors of any kind. Schwartz (2013) reported that adaptive responses to more prolonged stresses also occur. ...
The endocrine system as an indicator of stress and a means of evaluating animal welfare has been examined in this review. Stress endocrinology is an evolving area of study with many research questions to challenge scientists. However, for the past 25 years, the welfare of domestic animals has been an important aspect of animal science. Consequently, scientists have searched for objective ways to evaluate welfare, in that the demonstration of stress indicators could provide an objective information about how well farm animals kept under production conditions have adapted to the environment. Potential indicators have been suggested, both behavioural and physiological stress indicators among others. The endocrine system may be used as indicators of stress. The primary role of hormone may be a part of the homeostatic response to a stimulus (e.g. adrenaline, corticosteroids). The amplitude of hormone response may correlate with the severity of the stimulus. Moreover, a hormone may have a key role in normal body function (e.g. reproduction) and stress may deleteriously alter the hormone, signal prevents normal function. While stress inputs may reduce over time, hormone negative feedback is a major factor reducing hormone responses. This explains a reduction in perceived stimulus severity or habituation to the stimulus and the animal deemed "less stressed" and its welfare "better". With a better understanding of the basic biology, altered physiological processes involved in stress adaptability, it would be possible to assess and devise strategies for improving animal welfare.
... Several investigators have noted that psychological stress is associated with the development of CSCR (Agarwal et al., 2016;Bazzazi et al., 2015). Stress is associated with the activation of the hypothalamic-pituitaryadrenal axis, causing increased secretion of cortisol (Yanuzzi et al., 1987;Berger et al., 1987;Tsigos et al., 2002). ...
... Stress and Type A personality are associated with endogenous hypercortisolism. Stress activates the hypothalamic-pituitary-adrenal axis, causing increased secretion of cortisol (Tsigos et al., 2002;Stephens et al., 2012). Various studies, using standard stress assessment tools, have found the stress scores to be significantly elevated in CSCR patients as compared to the normal population (Agarwal et al., 2016;Bazzazi et al., 2015). ...
Introduction: Central serous chorioretinopathy (CSCR) is a disease with a multifactorial aetiology. Objectives: To evaluate the role of psychological stress and choroidal thickness in patients with CSCR. Materials and methods: This was a hospital-based, analytical cross-sectional study, conducted at Christian Medical College, Vellore, India, from 2018 February to 2019 September, after the approval of the Institutional Review Board and Ethics Committee. Patients who satisfied the eligibility criteria of the study, were selected from the outpatient clinics of the Department of Ophthalmology. Twenty-five patients with unilateral CSCR (Group 1 - cases), and 50 age and gender-matched patients without CSCR (Group 2 - controls), randomly selected in a 1:2 ratio, were enrolled after obtaining informed consent. Psychological stress was assessed using Cohen Perceived Stress Scale (PSS-10). All patients had a Swept Source optical coherence tomography scan of the macula. Subfoveal choroidal thickness (SFCT) of both eyes of all participants was measured using a standard protocol. The data were collated and analysed, using Independent samples t-test and Chi-square/ Fisher’s exact test, as appropriate, with IBM SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, N.Y., USA). Results: There was a significant difference between the two groups in mean stress scores (p <0.01), as well as stress categories (p <0.01). Although there was no significant difference in the prevalence of hypertension between the two groups (p = 0.33), there was a significant difference both in the mean systolic (p <0.01) and diastolic (p <0.01) blood pressure between the two groups. We found a significant difference between mean SFCT of CSCR eyes (421+/- 78.34 μm) and control eyes (314.24 +/- 52.48 μm, p <0.01), as well as between fellow eyes (396.20 +/- 68.79 μm) and control eyes (314.24 +/- 52.48 μm, p <0.01). However, there was no significant difference in the mean SFCT of CSCR eyes and fellow eyes (p =0.24). Conclusion: The findings reiterate the concept that the underlying pathophysiological changes leading to CSCR involve both the eyes of the patient. Psychological stress and hypertension may be factors that play an important role in the etiopathogenesis of the pachychoroid-related changes leading to CSCR. Stress relief measures, with a holistic approach to management, should be an integral part of the therapeutic strategies for CSCR.
... CRH, a 41-amino acid peptide, is observed to activate cAMP/MAPK pathway via CRF 1 (19,20). It is recognized as a primary regulator of the hypothalamic pituitary axis (HPA axis) (17,(21)(22)(23). The paraventricular nucleus (PVN) of the hypothalamus is the main source for CRH in the brain (17). ...
... The paraventricular nucleus (PVN) of the hypothalamus is the main source for CRH in the brain (17). CRH, UCNs and the two receptors are also reported to express widely in peripheral cells/tissues, being recognized as important cardiovascular peptides and immune/inflammatory molecules (23)(24)(25)(26)(27)(28). Their presence in gastrointestinal system has been detected for a long time since decades ago (29)(30)(31). ...
Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF1 and CRF2, with CRH mainly acting on CRF1, UCN1 on both CRF1 &CRF2 and UCN2-3 on CRF2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitis-associated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF1 plays a significant peripheral role in the development of colitis and CAC in that CRF1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review.
... The Hypothalamic-Pituitary-Adrenal (HPA) axis is an endocrine system that adapts the organism's ability to adjust homeostasis, for example by regulating glucocorticoids such as cortisol (Tsigos and Chrousos, 2002). It usually follows a diurnal rhythm. ...
Background: Constant availability, overtime and feeling overwhelmed by work can impact employees' wellbeing and their biological stress responses. Especially working parents often struggle to balance the demands of their work and family life and were found to be distracted from their work due to family responsibilities. The Family-to-Work Conflict (FWC) indicates the extent to which participating in work is made difficult by family demands. Recent studies have found associations between FWC and biological outcomes such as the Cortisol Awakening Response (CAR), a measure of an individual's Hypothalamic-Pituitary-Adrenal (HPA)-axis activity. This diary study investigates the effect of parental work demands on next day's cortisol response as well as the moderating role of FWC and the mediating role of fatigue.
Methods: Over the course of five consecutive days (from Monday to Friday), 168 observations were made on a total of 42 parents. Participants had at least one child and worked a minimum of 20 hours per week. Salivary cortisol samples were obtained immediately, 15 and 30 minutes after awakening each day. Work demands, FWC and fatigue were assessed using standardized questionnaires. Within-person effects were examined using multilevel modeling and mediation analyses.
Results: Our results indicate that there are no main effects of work demands on next day's cortisol response. The multilevel analysis revealed that FWC predicts lower wakening cortisol levels and confirmed FWC as an increasing moderator between work demands and next day's HPA-axis activity. Further, work overload was found to increase fatigue, which in turn leads to higher CAR on the following day. This indicates that fatigue mediates the relationship between work demands and CAR. Our findings add to a growing body of research demonstrating further predictors for HPA-axis activity and emphasise the importance of considering family related demands when investigating biological outcomes for working parents.
... Previous studies have found that irregular cycle variability has also been revealed to be significantly associated with antenatal depression [102]. The association between the menstrual cycle and depression could be supported by a possible biological mechanism, the hypothalamic-pituitary-adrenal axis, which is implicated in playing a role in regulating mood and responding to stress [103][104][105]. The number of total abortions is a contributing factor of postmenopausal depression. ...
Background
Depression is a prevalent mental health problem in postmenopausal women. Given its significant impact on the quality of life and overall well-being of postmenopausal women, there is need for a comprehensive review and meta-analysis of the existing research globally. This systematic review and meta-analysis evaluated the global prevalence of depression and potential associated factors in postmenopausal women.
Methods
The Cochrane Library, PubMed, EMBASE, Web of Science, MEDLINE, and PsycINFO databases were systematically searched from inception to March 22, 2023. The meta-analysis used the random-effects model to calculate the prevalence of depression rates and associated factors. In addition, subgroup analysis and sensitivity analysis were performed. Publication bias was assessed using funnel plots, Egger’s test, and nonparametric trim-and-fill tests.
Results
The meta-analysis included 50 studies that involved 385,092 postmenopausal women. The prevalence of depression in postmenopausal women was 28.00% (95% CI, 25.80–30.10). Among the factors relevant to depression among postmenopausal women, marital status (OR: 2.03, 95%CI: 1.33–3.11), history of mental illness (OR: 2.31, 95%CI: 1.50–3.57), chronic disease (OR: 3.13, 95%CI: 2.20–4.44), menstrual cycle (OR: 1.42, 95%CI: 1.17–1.72), abortion numbers (OR: 1.59, 95%CI: 1.40–1.80), menopausal symptoms (OR: 2.10, 95%CI: 1.52–2.90), and hormone replacement therapy (OR: 1.76, 95%CI: 1.31–2.35) were risk factors, while physical activity (OR: 0.56, 95%CI: 0.53–0.59), number of breastfed infants (OR: 0.43, 95%CI: 0.19–0.97), menopause age (OR: 0.44, 95%CI: 0.37–0.51) were preventive factors.
Conclusions
This study demonstrated that the prevalence of postmenopausal depression is high, and some risk factors and protective factors associated with it have been identified. It is necessary to improve screening and management and optimize prevention and intervention strategies to reduce the harmful effects of postmenopausal depression.
... The hypothalamic-pituitary-adrenal axis is the efferent stress axis that interrelates the adaptive responses of the human body to stressors and is a part of the limbic system, the area predominantly involved in emotional responses and memory [47]. ...
Misophonia is a neurophysiological disorder with behavioral implications, is complex and multifactorial in origin, and is characterized by an atypical and disproportionate emotional response to specific sounds or associated visual stimuli. Triggers include human-generated sounds, mainly sounds related to feeding and breathing processes, and repetitive mechanical sounds. In response to the triggering stimulus, the patient experiences immediate, high-intensity, disproportionate physical and emotional reactions that affect their quality of life and social functioning. The symptoms of misophonia can occur at any age, but onset in childhood or adolescence is most common. Affected children live in a constant state of anxiety, suffer continuous physical and emotional discomfort, and are thus exposed to significant chronic stress. Chronic stress, especially during childhood, has consequences on the main biological systems through the dysregulation of the hypothalamic–pituitary–adrenal axis, including the gastrointestinal tract. Here, we provide arguments for a positive correlation between misophonic pathology and gastrointestinal symptoms, and this hypothesis may be the starting point for further longitudinal studies that could investigate the correlations between these childhood vulnerabilities caused by misophonia and their effect on the gastrointestinal system. Further research to study this hypothesis is essential to ensure correct and timely diagnosis and optimal psychological and pharmacological support.
... In the first place, the onset of fatigue and its co-factors is regulated by the in-vivo stress response system [101,102]. When subjected to internal and external stress, the biological stress response system immediately makes corresponding alterations, including the HPA axis and the ANS system, as well as the neuroimmune system [14,[103][104][105]. Sustained stress may lead to maladaptive responses manifested as dysregulation of the above systems [106], which is specifically manifested as abnormal levels of serum catecholamines and glucocorticoids and persistent low-grade inflammation based on findings such as microglial activation in the brain and increased pro-inflammatory cytokines in the periphery [107]. ...
Fatigue, an increasingly acknowledged symptom in various chronic diseases, has garnered heightened attention, during the medical era of bio-psycho-social model. Its persistence not only significantly compromises an individual’s quality of life but also correlates with chronic organ damage. Surprisingly, the intricate relationship between fatigue and female reproductive health, specifically infertility, remains largely unexplored. Our exploration into the existing body of evidence establishes a compelling link between fatigue with uterine and ovarian diseases, as well as conditions associated with infertility, such as rheumatism. This observation suggests a potentially pivotal role of fatigue in influencing overall female fertility. Furthermore, we propose a hypothetical mechanism elucidating the impact of fatigue on infertility from multiple perspectives, postulating that neuroendocrine, neurotransmitter, inflammatory immune, and mitochondrial dysfunction resulting from fatigue and its co-factors may further contribute to endocrine disorders, menstrual irregularities, and sexual dysfunction, ultimately leading to infertility. In addition to providing this comprehensive theoretical framework, we summarize anti-fatigue strategies and accentuate current knowledge gaps. By doing so, our aim is to offer novel insights, stimulate further research, and advance our understanding of the crucial interplay between fatigue and female reproductive health.
... Additionally, evidence from animal studies strongly suggests that the HPT axis significantly influences 5-HT neurotransmission in the adult brain (Bauer et al., 2002). Secondly, several lines of evidence suggested a dysregulation of the HPA axis stress response activity in suicidal patients (O'Connor et al., 2020;Tsigos & Chrousos, 2002). Prolonged stress responses in the HPA axis could hinder HPT function, resulting in decreased FT4 and subsequently increased TSH levels (Duval et al., 2002). ...
Background
This study aimed to investigate sex differences in risk factors for suicide attempts in first‐episode and drug naive (FEDN) major depressive disorder (MDD) with comorbid subclinical hypothyroidism (SCH).
Methods
A total of 1034 FEDN MDD patients with comorbid SCH were enrolled. The Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Positive and Negative Syndrome Scale (PANSS) positive subscale were used to assess patients’ symptoms. Thyroid hormone levels and metabolic parameters were measured.
Results
MDD patients with SCH had a significantly higher risk of suicide attempts than those without SCH (25.4% vs. 12.2%). Logistic regression showed that HAMA score, thyroid stimulating hormone (TSH) levels, and thyroid peroxidase antibody (TPOAb) levels were significantly associated with an increased risk for suicide attempts in both male and female MDD patients comorbid SCH, while low‐density lipoprotein cholesterol (LDL‐C) was significantly associated with an increased risk for suicide attempts only in male patients, HAMD score and systolic blood pressure were significantly associated with an increased risk for suicide attempts only in female patients.
Conclusion
SCH comorbidities may increase suicide attempts in MDD patients. Our results showed significant sex differences in clinical and metabolic factors associated with suicide attempts among FEDN MDD patients with comorbid SCH, highlighting appropriate sex‐based preventive interventions are needed.
... Indeed, Poorman et al. reported higher rate of osteoporosis, rheumatoid arthritis, and connective tissue disorders in patients undergoing surgery for cervical deformity [37]. Furthermore, depressive symptoms can influence patients' adherence to prescribed medical regimens, affecting their biological milieu through neuroendocrine and inflammatory mechanisms [38,39]. This not only impedes the healing process but may also contribute to heightened susceptibility to complications. ...
Introduction: The relationship between psychiatric disorders, including depression, and invasive interventions has been a topic of debate in recent literature. While these conditions can impact the quality of life and subjective perceptions of surgical outcomes, the literature lacks consensus regarding the association between depression and objective perioperative medical and surgical complications, especially in the neurosurgical domain. Methods: MEDLINE (PubMed), EMBASE, PsycINFO, and the Cochrane Library were queried in a comprehensive manner from inception until 10 November 2023, with no language restrictions, for citations investigating the association between depression and length of hospitalization, medical and surgical complications, and objective postoperative outcomes including readmission, reoperation, and non-routine discharge in patients undergoing spine surgery. Results: A total of 26 articles were considered in this systematic review. Upon pooled analysis of the primary outcome, statistically significantly higher rates were observed for several complications, including delirium (OR:1.92), deep vein thrombosis (OR:3.72), fever (OR:6.34), hematoma formation (OR:4.7), hypotension (OR:4.32), pulmonary embolism (OR:3.79), neurological injury (OR:6.02), surgical site infection (OR:1.36), urinary retention (OR:4.63), and urinary tract infection (OR:1.72). While readmission (OR:1.35) and reoperation (OR:2.22) rates, as well as non-routine discharge (OR:1.72) rates, were significantly higher in depressed patients, hospitalization length was comparable to non-depressed controls. Conclusions: The results of this review emphasize the significant increase in complications and suboptimal outcomes noted in patients with depression undergoing spinal surgery. Although a direct causal relationship may not be established, addressing psychiatric aspects in patient care is crucial for providing comprehensive medical attention.
... For example, striped mice (Rhabdomys pumilio) expressing stereotypic behaviours have higher reproduction performance than striped mice without stereotypic behaviours (16); cows with stereotypic behaviours also produce more milk than normal cows (10). When animals are stressed, the hypothalamic-pituitaryadrenal (HPA) axis and locus coeruleus-norepinephrine (LC-NE) axis in the organism are activated, as evidenced by a rapid increase in the concentrations of glucocorticoids (e.g., cortisol and corticosterone) and catecholamines (e.g., dopamine) in the body (17,18). In mammals, the concentration of cortisol is often used as an indicator of stress in the body (19). ...
Introduction
Stereotypic behaviours, especially oral stereotypic behaviours, are frequently expressed in farm animals. Tongue-rolling is the most common oral stereotypic behaviour in dairy cows (Bos taurus). If animals frequently display stereotypic behaviours, this is an indication of poor welfare. It has been suggested that animals express stereotypic behaviours as a way of coping with stress. As a result, animals with stereotypic behaviours may have lower levels of stress hormones than animals without stereotypic behaviours.
Methods
In this study, 916 Holstein cows in the first lactation were subjected to scan sampling behavioural observations 200 times for 10 days. All cows were assigned to either a stereotypic behaviours group (SB) or a control group (CON). The SB group was further subdivided into a tongue-rolling group (TR) and an other-stereotypic behaviours group (OS). The TR group was also split into an only tongue-rolling group (OTR) and a mixed tongue-rolling and other stereotypic behaviours group (TROS). Some cows in the TR group belonged to an extreme tongue-rolling group (ETR). Hair and saliva samples were collected from 601 cows to test cortisol concentrations and dairy herd improvement (DHI) data were collected from a total of 762 cows.
Results
There were no differences in hair or saliva cortisol concentrations between the groups (p>0.05), and the frequencies of tongue-rolling were not associated with cortisol concentrations (p>0.05). For DHI in cows, the milk protein percentage (p = 0.028), milk true protein percentage (p = 0.021) and milk crude protein percentage (p = 0.023) of cows in the ETR group were significantly lower than those in the CON group. For cows in ETR group, as the frequencies of tongue-rolling increased, the milk protein percentage (p = 0.034, r = 0.365), milk true protein percentage (p = 0.022, r = 0.393) and milk crude protein percentage (p = 0.035, r = 0.363) increased.
Discussion
We investigated the relationship between stereotypic behaviours and stress by using a non-invasive sampling method to minimise harm to the cows. We suggest that tongue-rolling may not be a way for cows to cope with stress, at least in terms of cortisol concentrations.
... Social rejection occurs when others ostracize, exclude, or ignore an individual from a oneon-one or group interaction (Leary, 2010;Leary & Leder, 2009). The experience of social rejection can activate the hypothalamic-pituitary-adrenal (HPA) axis, the body's stress response system, which regulates the secretion of cortisol, a stress-sensitive hormone (Tsigos & Chrousos, 2002). In response to social rejection, girls exhibit greater cortisol reactivity relative to boys, which may place them at risk for a host of mental health conditions, most notably, internalizing problems (Stroud et al., 2002. ...
Background
The perseverative cognition hypothesis stipulates that rumination (repetitive, passive, uncontrollable negative thinking) prolongs the experience of a stressor which impacts stress physiology. In line with this hypothesis, we proposed that in response to real-life experiences of social rejection, adolescent girls who ruminate would show a blunted diurnal cortisol slope the next day relative to girls who do not ruminate. We also examined the effects of social rejection and rumination on waking cortisol levels and the cortisol awakening response.
Method
Participants were (n = 50) adolescent girls (mean age = 13.30, SD = 2.34) who varied on psychiatric risk and provided saliva samples 4 times a day for 3 days, as well as, daily diary reports of social rejection and rumination. A lagged multilevel model was utilized to examine the interactive effects of rejection and rumination on diurnal cortisol.
Results
There was a significant interaction between social rejection and rumination. Specifically, rumination following social rejection was associated with a flatter diurnal cortisol slope. In the absence of rumination, social rejection was marginally associated with a steeper diurnal cortisol slope. The effects for waking cortisol levels and the cortisol awakening response were null.
Conclusion
Findings support the perseverative cognition hypothesis and suggest that cognitive mechanisms such as rumination can impact stress physiology.
... In humans, cortisol (11b,17a,21-trihydroxypregn-4ene-3,20-dione) is a key glucocorticoid in the endocrine and stress response systems and is secreted via the hypothalamic-pituitary-adrenal (HPA) axis [15]. The central control of the HPA axis is very complex and vital for the neuroendocrine system, which regulates the rhythm of daily hormone secretion and influences many physiological functions to respond appropriately to the changing environments [16]. ...
Acute sleep deprivation has aroused widespread concern and the relationship between acute sleep deprivation and cortisol levels is inconsistent. This study aimed to explore additional evidence and details. The PubMed, Web of Science, EMBASE, CLINAHL and Cochrane databases were searched for eligible studies published up to June 7, 2023. All analyses were performed using Review Manager 5.4 and Stata/SE 14.0. A total of 24 studies contributed to this meta-analysis. There was no significant difference in cortisol levels between participants with acute sleep deprivation and normal sleep in 21 crossover-designed studies (SMD = 0.18; 95% CI: –0.11, 0.45; p = 0.208) or 3 RCTs (SMD = 0.26; 95% CI: –0.22, 0.73; p = 0.286). Subgroup analysis revealed that the pooled effects were significant for studies using serum as the sample (SMD = 0.46; 95%CI: 0.11, 0.81; p = 0.011). Studies reporting cortisol levels in the morning, in the afternoon and in the evening did not show significant difference (p > 0.05). The pooled effects were statistically significant for studies with multiple measurements (SMD = 0.28; 95%CI: 0.03, 0.53; p = 0.027) but not for studies with single cortisol assessments (p = 0.777). When the serum was used as the test sample, the cortisol levels of individuals after acute sleep deprivation were higher than those with normal sleep.
... Stress, in particular, may play a detrimental role in the dysregulation of the hippocampus-pituitary-adrenal (HPA) axis [65,66] and the sympathetic-adrenal-medullary (SAM) pathway [67]. The activation of the HPA axis due to chronic stress results in the release of cortisol into the blood via a complex signalling cascade [68], whilst the SAM pathway is activated by the stimulation of the adrenal medulla to release the catecholamines epinephrine and norepinephrine [67]. ...
The nature versus nurture debate has intrigued scientific circles for decades. Although extensive research has established a clear relationship between genetics and disease development, recent evidence has highlighted the insufficiency of attributing adverse health outcomes to genetic factors alone. In fact, it has been suggested that environmental influences, such as socioeconomic position (SEP), may play a much larger role in the development of disease than previously thought, with extensive research suggesting that low SEP is associated with adverse health conditions. In relation to oral health, a higher prevalence of caries (tooth decay) exists among those of low SEP. Although little is known about the biological mechanisms underlying this relationship, epigenetic modifications resulting from environmental influences have been suggested to play an important role. This review explores the intersection of health inequalities and epigenetics, the role of early-life social adversity and its long-term epigenetic impacts, and how those living within the lower hierarchies of the socioeconomic pyramid are indeed at higher risk of developing diseases, particularly in relation to oral health. A deeper understanding of these mechanisms could lead to the development of targeted interventions for individuals of low SEP to improve oral health or identify those who are at higher risk of developing oral disease.
... Cortisol, a steroid hormone produced by the adrenal cortex, plays a role in stress response, glucose metabolism, and immune function (Tsigos and Chrousos, 2002). Interactions with companion animals can also regulate human cortisol levels. ...
The impact of companion animals on human psychological health has garnered widespread attention. Research demonstrates that companion animals contribute positively in various ways, including reducing depression, anxiety, stress, and fostering positive emotions in humans. Recent studies have revealed significant changes in the activity levels of human emotion-related cortical areas (such as the frontal cortex and amygdala) and neurotransmitter (e.g., oxytocin, cortisol) secretion due to interaction with companion animals. However, research in this domain is still in a nascent stage, with many unknowns in the cognitive neural mechanisms involved. This paper proposes that to understand the cognitive mechanisms through which companion animals affect human psychological health, we need to examine changes in emotional cognitive processing. It aims to uncover the neurological underpinnings of how companion animals enhance human psychological well-being from the perspective of brain connectivity. This approach is expected to provide theoretical support and direction for future research and practical applications in this field.
... 18 The amygdala encodes and stores fear memory after receiving sensory input from the thalamus, which also consolidates and retrieves memories from the initial stimuli that induce fear (199)(200)(201). Fear memory is associated with the release of stress hormones such as adrenaline and cortisol, which stimulate the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis (39,(202)(203)(204)(205). This study does not show evidence of fear memory acquisition. ...
The study explores the role of the kat2 gene in behavior, particularly in relation to psychiatric disorders like PTSD. The KAT II enzyme is responsible for the production of kynurenic acid, a tryptophan metabolism byproduct. In kat2 knockout mice, experience-based depressive-like behaviors, emotional indifference, motor deficits, and changes in tryptophan metabolism were observed. These changes are accompanied by a shift towards a different metabolic pathway and a decrease in a gut microbial metabolite, indicating an oxidative and excitotoxic stress. This is the first evidence linking the deletion of the kat2 gene to depression-like behaviors and may provide insights into the relationship between tryptophan metabolism and PTSD.
... Moreover, there were no significant changes in the plasma corticosterone levels, which are the major stress hormones [55]. These results suggest that long-term exposure to these low concentrations of high molecular weight odorants causes an increase in hypothalamic β-endorphin levels without stress-induced stimulation of the hypothalamus pituitary anterior lobe-adrenal cortex (HPA) axis in rats [55,69]. Moreover, long-term exposure increase the hypothalamic β-endorphin levels in rats [55]. ...
... Research demonstrates that administering melatonin can alleviate skin lesions, reduce scratching, and lower serum IgE levels in ADstressed models 65 . Interestingly, psychological relaxation has been proven to enhance the recovery of the skin's protective barrier 66,67 . Skin inflammation can pave the way for secondary bacterial infections, and relaxation techniques can curtail the production of antimicrobial peptides (AMPs), thereby increasing the risk of severe skin infections 68,69,70 . ...
The genesis of chronic skin illnesses is intricately intertwined with genetics, the environment, psychological and the immune system. However, recent studies have shown that mental health issues can exacerbate and control the severity of chronic skin disorders. Focusing on illnesses including psoriasis, atopic dermatitis, and urticaria, this article seeks to evaluate and discuss the current literature on the interplay of psychological aspects in chronic skin diseases. Here, we investigate the two-way connection between emotional discomfort (such as stress, worry, or depression) and the physiology of various skin conditions. Furthermore, we address possible mechanisms underlying the link between mental health and skin diseases, which will help the physicians to select the medicines and treatment approach.
... [1] In response to stress conditions, human body produces many neurotransmitters and hormones, and cortisol is probably the most important. [2] Physiological cortisol levels are not constant and depend by the hours of the day. In particular, it can be found in many biological fluids, such as saliva, sweat, serum, plasma, urine and hairs, with a wide range of concentration, [3] from 10-250 pg/mg in hair and plasma, [4] to 0.1-12 ng/mL in blood and saliva, [5] to 10-150 mg/die in urine. ...
During a stress condition, the human body synthesizes catecholamine neurotransmitters and specific hormones (called “stress hormones”), the most important of which is cortisol. The monitoring of cortisol levels should be extremely important to control the stress levels, and for this reason, it shows important medical applications. The common analytical methods (HPLC, GC‐MS) cannot be used in real life, due to the bulky size of the instruments and the necessity of specialized personnel. Molecular probes solve these problems due to their fast and easy use. The synthesis of new fluorescent rhodamine probes, able to interact by non‐covalent interactions with cortisol, the recognition properties in solution as well as in solid state by Strip Test, using a smartphone as detector, are here reported. DFT calculations and FT‐IR measurements suggest the formation of supramolecular complexes through hydrogen bonds as main non‐covalent interaction. The present study represents one of the first sensor, based on synthetical chemical receptors, able to detect cortisol in a linear range from 1 mM to 1 pM, based on non‐covalent molecular recognition and paves the way to the realization of practical point‐of‐care device for the monitoring of cortisol in real live.
... Esses sistemas podem atuar como um marca-passos para as transições de desenvolvimento e manutenção, influenciando a defesa contra doenças, o desempenho cognitivo, a resiliência ao estresse, a compulsão e o autocontrole. (Tsigos, 2002;MacMillan, 2009). ...
This review describes how risk factors and adversities predispose to metabolic syndrome and chronic diseases, acting through harmful habits, nutritional changes, toxins, pollutants, inflammations, pathogens and chronic stress. Such conditions are correlated to fast environment driven by life history strategies as responses to the tensions and impacts witnessed, maintaining a close link between risks and metabolic syndromes throughout life and even between generations.
... 65 CRHR1 is the receptor of corticotropin-releasing hormone (CRH), which stimulates the secretion of adrenocorticotropin hormone (ACTH) when bound. 66 HSP90AA1 is a molecular chaperone protein that regulates hormone signaling in response to stress. 67 NR3C1 is a glucocorticoid receptor that when bound by cortisol negatively regulates CRH and ACTH production. ...
Background:
Bronchopulmonary dysplasia (BPD), a common morbidity among very preterm infants, is associated with chronic disease and neurodevelopmental impairments. A hypothesized mechanism for these outcomes lies in altered glucocorticoid (GC) activity. We hypothesized that BPD and its treatments may result in epigenetic differences in the hypothalamic-pituitary-adrenal (HPA) axis, which is modulated by GC, and could be ascertained using an established GC risk score and DNA methylation (DNAm) of HPA axis genes.
Methods:
DNAm was quantified from buccal tissue (ECHO-NOVI) and from neonatal blood spots (ELGAN ECHO) via the EPIC microarray. Prenatal maternal characteristics, pregnancy complication, and neonatal medical complication data were collected from medical record review and maternal interviews.
Results:
The GC score was not associated with steroid exposure or BPD. However, six HPA genes involved in stress response regulation demonstrated differential methylation with antenatal steroid exposure; two CpGs within FKBP5 and POMC were differentially methylated with BPD severity. These findings were sex-specific in both cohorts; males had greater magnitude of differential methylation within these genes.
Conclusions:
These findings suggest that BPD severity and antenatal steroids are associated with DNAm at some HPA genes in very preterm infants and the effects appear to be sex-, tissue-, and age-specific.
Impact:
This study addresses bronchopulmonary dysplasia (BPD), an important health outcome among preterm neonates, and interrogates a commonly studied pathway, the hypothalamic-pituitary-adrenal (HPA) axis. The combination of BPD, the HPA axis, and epigenetic markers has not been previously reported. In this study, we found that BPD itself was not associated with epigenetic responses in the HPA axis in infants born very preterm; however, antenatal treatment with steroids was associated with epigenetic responses.
... Maintaining physical fitness can improve mental health through the common inflammatory and neurochemical pathways; the neurochemical effects of physical fitness reduce the risk of the onset of particular mental disorders [48][49][50]. On the other hand, the opposite explanation (i.e., having a mental disorder may be a barrier to physical fitness) also accounts for the observed impacts of physical fitness on mental health [51]. ...
Background
The physical and mental health of college students is often mentioned, but there is limited research on a direct relationship between the mental health status of college students and their physical fitness level. This study mainly proves the relationship between Chinese college students’ mental health and physical fitness indicators.
Method
This study collected SCL-90 Scale test results from 5262 students (4012 boys and 1250 girls) through a questionnaire survey and conducted a Sport Quality Test on these students. Statistical software SPSS was applied for differential analysis and logistic regression analysis. Specifically, the differences in sport quality indicators between normal and abnormal mean total scores of psychological tests were analyzed first. Then, the binary logistic regression model was used to explore the impacts of sports quality indicator scores on students’ psychological fitness.
Results
There are differences in the results of physical fitness tests between students with abnormal psychology and students with normal psychology. The four indexes of students’ vital capacity, speed, explosive power of lower limbs, and endurance running are effective in improving students’ psychologically abnormal state, and endurance running and improving vital capacity are the most effective methods to improve students’ psychologically abnormal state. In the physical tests of Chinese college students, the risk of psychological abnormalities was reduced by 9% for every one-point increase in lung capacity and 10.4% for every one-point increase in endurance running performance.
Conclusions
Chinese college students’ physical fitness and mental health are related. The best methods for treating psychological disorders are lung capacity improvement and endurance running. According to the physical test results of Chinese college students, for every 1-point increase in lung capacity and endurance running, the risk of psychological abnormalities decreased by 9% and 10.4%, respectively.
... Studies indicate that lower levels of WB are linked with an increased risk for cardiovascular disease and mortality (Chalmers et al., 2014), while higher levels are associated with resilience and the ability to recover from stressors and negative experiences (Fredrickson, 2004). Indeed, stress is a key disruptor of WB, affecting the balance between the sympathetic (SNS) and parasympathetic (PNS) branches of the autonomic nervous system (ANS) and activating the hypothalamic-pituitary-adrenal axis (Tsigos and Chrousos, 2002). While acute stress can be beneficial by increasing lucidity, performance, and chances of survival, chronic stress results in cognitive and emotional disruptions, including reduced cognitive flexibility and increased negative bias and mental disorders (e.g., depression and anxiety). ...
Wearable electroencephalography (EEG) and electrocardiography (ECG) devices may offer a non-invasive, user-friendly, and cost-effective approach for assessing well-being (WB) in real-world settings. However, challenges remain in dealing with signal artifacts (such as environmental noise and movements) and identifying robust biomarkers. We evaluated the feasibility of using portable hardware to identify potential EEG and heart-rate variability (HRV) correlates of WB. We collected simultaneous ultrashort (2-minute) EEG and ECG data from 60 individuals in real-world settings using a wrist ECG electrode connected to a 4-channel wearable EEG headset. These data were processed, assessed for signal quality, and analyzed using the open-source EEGLAB BrainBeats plugin to extract several theory-driven metrics as potential correlates of WB. Namely, the individual alpha frequency (IAF), frontal and posterior alpha asymmetry, and signal entropy for EEG. SDNN, the low/high frequency (LF/HF) ratio, the Poincare SD1/SD2 ratio, and signal entropy for HRV. We assessed potential associations between these features and the main WB dimensions (hedonic, eudaimonic, global, physical, and social) implementing a pairwise correlation approach, robust Spearman's correlations, and corrections for multiple comparisons. Only 8 files showed poor signal quality and were excluded from the analysis. Eudaimonic (psychological) WB was positively correlated with SDNN and the LF/HF ratio. EEG posterior alpha asymmetry was positively correlated with Physical WB (i.e., sleep and pain levels). No relationships were found with the other metrics or between EEG and HRV metrics. These physiological metrics enable a quick, objective assessment of well-being in real-world settings using scalable, user-friendly tools.
... In response to stress, the body initiates a primary mechanism triggered by internal and external stressors. The body processes the stress-related information and generates a response commensurate with the perceived threat level, whereby the amygdala, a key brain region, signals the brain stem to release sympathetic adrenergic catecholamines, namely, epinephrine and norepinephrine (Tsigos & Chrousos, 2002). These neurotransmitters, upon entering the bloodstream, prompt a series of physiological changes. ...
Examining the impact of the environment on the mental health of older adults is crucial in our aging society. Existing research on the restorative benefits of forests has largely overlooked older adults and, in most cases, focused only on group forest visits, which were restricted during the COVID-19 pandemic. This study explores the effects of individual walks on the mental health of adults aged 60 years or older in Slovakia. Through a randomized intervention study, participants were divided into groups walking in either forests or urban areas for 40 minutes over a month. The forest walking group exhibited significant improvements in cognitive flexibility, heart rate variability, and reduced acute and relative chronic stress levels, documented by Trail Making Test, photoplethysmography, and both salivary and hair cortisol measurements, respectively. The results were associated with forests featuring high species diversity and complex forest structures, typical in mixed forests with old trees. The respective patterns originated from natural processes or were achieved by more and less intense management for recreational purposes, illustrating manifold ways to ensure the desired, health- and subjective well-being-centered cultural ecosystem services of forests, specifically reflecting specific needs of older adults in the cognitive health domain.
While urban walking also benefits various quality-of-life aspects, forest walking is particularly notable for cognitive function enhancement. However, urban walking may be more suitable, convenient, or safer for frail older individuals, considering their sensitivity to factors impacting physical health. Specifically, walking in urban areas may be similarly beneficial as forest walking with regard to most of the quality-of-life components. However, when choosing between options available for walking in both forest and urban settings, the study findings strongly favor the former. The results underscore health- and subjective well- being-centered cultural ecosystem services of forests as crucial mental health support, including during crises for vulnerable groups like older adults. Integrating nature-based activities into mental health plans, specifically for these groups, is recommended. Collaboration between public health and forest management experts is vital to develop scalable frameworks focused on safe and accessible forest areas for older adults. Nature- based therapy enhances vitality and productivity in an extended retirement age context while ensuring green spaces benefit both individual and planetary well-being.
Keywords: forest and urban walking, older adults, cognitive flexibility, stress.
Background: Memory and emotion are highly vulnerable to psychiatric disorders like post-traumatic stress disorder (PTSD), which has been linked to serotonin (5-HT) metabolism disruptions. In fact, over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) metabolic pathway, producing a variety of bioactive molecules. The aadat (kat2) gene encodes mitochondrial kynurenine aminotransferase (KAT) isotype 2, responsible for kynurenic acid (KYNA) production. Little is known about its role in behavior.
Methods: In CRISPR/Cas9-induced aadat knockout (kat2−/−) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and the urine of 8-week-old males compared to wild-type mice.
Results: Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: KYN, antioxidant KYNs, 5-hydroxyindolacetic acid, and indole-3-acetic acid levels are lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase are lower, but kynurenine 3-monooxygenase is higher; and oxidative stress and excitotoxicity indices are higher.
Conclusion: Transgenic mice show depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-HK pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite. This is the first evidence that deleting the aadat gene causes depression-like behaviors that are unique to despair experience, which appears to be linked to excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in experience-based depression, better understanding of these complex conditions, and more effective therapeutic strategies by elucidating the relationship between Trp metabolism and PTSD pathogenesis.
Introduction. A comparative assessment of the reactivity of cerebral energy metabolism (CEM) under stress will allow us to determine the features of the course of vibration disease (VD) caused by exposure to various types of vibration. The study aims to consider the features of the reactivity of the cerebral energy metabolism (CEM) in patients with vibration disease, depending on the type of vibration exposure. Materials and methods. The researchers studied the features of adaptation under stress using the method of neuroenergetic mapping (NEM) with measurement of the level of constant potential (LCP). Groups were formed: I (n=58) — patients with VD due to the effects of local vibration (VDloc), II (n=50) — with VD associated with the combined effects of local and general vibration (VDcomb), III (n=39) — a comparison group. Results. The authors found that for patients with VDloc and VDcomb it is characterized by a rapid rigid reaction to physical and emotional stress. In patients with VD, regardless of the type of vibration exposure, there was a predominance of negative reactions of cerebral energy metabolism to physical activity compared with emotional activity. The restoration of cerebral energy metabolism in the post-hyperventilation period in the predominant number of patients has a disorder of autonomic autoregulation of the constancy of internal functions, which creates equal risks of the formation of comorbid pathology in both VDloc and VDcomb. Limitations. The study is limited to a sample of patients, an integrated approach based on modern diagnostic methods, and the use of multidimensional exploratory analysis methods. Conclusion. The results obtained substantiate the independence of the adaptive reactivity of cerebral energy metabolism from the type of vibration exposure and indicate the predominance of a rigid reaction variant characterizing the disorder of adaptive reactions according to the asthenic type. Ethics. The examination of patients was conducted in accordance with the ethical standard of the Helsinki Declaration of the World Medical Association "Ethical Principles of conducting scientific medical research with human participation" as amended in 2000 and the "Rules of Good Clinical Practice" (approved by Order of the Ministry of Health of the Russian Federation No. 200n on 04/01/2016). All the surveyed signed an informed consent to participate in the study. There is a conclusion of the local Ethics Committee (Protocol No. 5 dated 03/21/2023).
Background
The hypothalamus, a small yet crucial neuroanatomical structure, integrates external (e.g., environmental) and internal (e.g., physiological/hormonal) stimuli. This integration governs various physiological processes and influences cognitive, emotional, and behavioral outcomes. It serves as a functional bridge between the nervous and endocrine systems, maintaining homeostasis and coordinating bodily functions.
Summary
Recent advancements in the neurobiology of the hypothalamus have elucidated its functional map, establishing a causal relationship between its responses—such as respiration, sleep, and stress—and various physiological processes. The hypothalamus facilitates and coordinates these complex processes by processing diverse stimuli, enabling the body to maintain internal balance and respond effectively to external demands. This review delves into the hypothalamus’s intricate connections with cognition, emotion, and physiology, exploring how these interactions promote overall well-being and adaptability.
Key Message
Targeted external stimuli can modulate hypothalamic neuronal activities, impacting the physiological, cognitive, and emotional landscape. The review highlights non-invasive techniques, such as controlled breathing exercises, optimized sleep architecture, and stress management, as potential methods to enhance hypothalamic function. Ultimately, this comprehensive review underscores the multifaceted role of the hypothalamus in integrating signals, maintaining homeostasis, and influencing cognition, emotion, and physiology.
Type II diabetes (T2D) is a multifaceted metabolic disease influenced by various factors (genetic, epigenetic, environmental, and other). An alarming surge in T2D prevalence is estimated, reaching 700 million cases by 2045 worldwide. This review explores the complex interactions of multiple risk factors throughout life and offers a new perspective on T2D. Genetic and epigenetic influences are described in detail. Prenatal factors, such as exposure to undernutrition and maternal overfeeding, induce lasting epigenetic changes, affecting T2D susceptibility. Furthermore, birthweight is a crude proxy for perinatal programming, with low and high birthweights associated with increased T2D risk. Often overlooked, the early postnatal period also significantly contributes to perinatal programming. Neonatal over-nutrition and feeding choices exert lasting effects on DNA methylation and metabolic outcomes later in life. Stress during this period further exacerbates T2D susceptibility. In continuation, childhood behaviors which are influenced by prior periods contribute substantially to T2D risk. Adverse childhood experiences amplify the risk of many diseases, including T2D. Sleep hygiene throughout life plays a role in metabolic health, influencing insulin resistance and appetite regulation. In adulthood, obesity remains a prominent predictor of T2D, with chronic stress contributing to weight gain and unhealthy lifestyle. This review proposes a novel perspective, considering T2D pathophysiology as a nonlinear process governed by numerous factors and their interactions throughout life. The inherent unpredictability suggests a need for personalized interventions tailored to specific risk profiles, emphasizing the importance of understanding gene-environment interactions and embracing a holistic view of T2D pathogenesis.
Background and objective
Psychological stress has been identified in some observational studies as a potential factor that may modify and affect periodontal diseases, but there are no similar data for peri-implantitis. The aim of this study was to determine the relationship between interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)α inflammatory cytokines and the psychological stress-related markers, glucocorticoid receptor-α (GRα), and salivary α-amylase (sAA) gene expression levels in saliva samples obtained from healthy implants and peri-implantitis patients.
Materials and methods
The study included a total of 50 systemically healthy subjects. Peri-implant clinical parameters were recorded and psychological stress level was evaluated with the hospital anxiety and depression scale (HAD) and state-trait anxiety inventory (STAI) questionnaire forms. Following the evaluations, the patients were divided into 4 groups according their stress and clinical status (Ia, Ib, IIa, IIb). IL-1β, IL-6, IL-10, IFNα, GRα, sAA gene expression levels in the saliva samples were quantified by quantitative polymerase chain reaction (qPCR).
Results
In the group of peri-implantitis who had a high score in stress level assessment scales, significantly higher IL-1β, IL-6, sAA expression levels were observed (p < 0.001). The IL-10 gene expression levels were lower in the groups with a high score in the stress level assessment scales (p < 0.001). GRα gene was expressed at lower levels in the group of peri-implantitis who had a high score in stress level assessment scales but the difference was not statistically significant (p = 0.065).
Conclusion
The study findings suggest that psychological stress may increase the inflammation associated with peri-implantitis by affecting cytokine expression levels.
Clinical relevance
To prevent peri-implantitis or reduce its prevalence, it could be beneficial to evaluate stress levels and identify individuals experiencing stress.
The intestines of animals are a complex ecosystem consisting of a microbiome, host cells, and nutrients. There are about 100 trillion bacteria in the intestinal tract that form the intestinal microbiota. They are taxonomically classified by genus, family, order, and type. The intestinal microflora mainly consists of six types: Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, Fusobacteria and Verrucomicrobia. Bacterioidetes and firmicutes occupy a dominant position in the intestinal tract of animals and play a key role in the nutrient absorption system and help strengthen the intestinal barrier. The composition of the microbial community ecosystem is dynamic, and its composition depends on many factors including genes, medications, and feeding.
The purpose of this review is to analyze the microbiome of the gastrointestinal tract of animals and factors affecting their biodiversity. The composition of the microbial community ecosystem is dynamic and depends on many factors, including genes, medications, and feeding. Changes in the feeding diet can cause time shifts (within 24 hours) in a large number of microorganisms. It follows that feeding is also a vital regulator of the intestinal microbiota. The prospects for applying the results of the study of the microbiota of the body of farm animals are obvious, since they can become the basis for creating technologies that allow correcting undesirable changes in the microbiome of animals that arise as negative consequences of the intensification of highly productive agricultural production.
During parturition and the immediate post-partum period there are two opposite, yet interdependent and intertwined systems that are highly active and play a role in determining lifelong health and behaviour in both the mother and her infant: the stress and the anti-stress (oxytocin) system. Before attempting to understand how the environment around birth determines long-term health trajectories, it is essential to understand how these two systems operate and how they interact. Here, we discuss together the hormonal and neuronal arms of both the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic systems and how they interact. Although the HPA axis and glucocorticoid stress axis are well studied, the role of oxytocin as an extremely powerful anti-stress hormone deserves more attention. It is clear that these anti-stress effects depend on oxytocinergic nerves emanating from the supraoptic nucleus (SON) and paraventricular nucleus (PVN), and project to multiple sites at which the stress system is regulated. These, include projections to corticotropin releasing hormone (CRH) neurons within the PVN, to the anterior pituitary, to areas involved in sympathetic and parasympathetic nervous control, to NA neurons in the locus coeruleus (LC), and to CRH neurons in the amygdala. In the context of the interaction between the HPA axis and the oxytocin system birth is a particularly interesting period as, for both the mother and the infant, both systems are very strongly activated within the same narrow time window. Data suggest that the HPA axis and the oxytocin system appear to interact in this early-life period, with effects lasting many years. If mother-child skin-to-skin contact occurs almost immediately postpartum, the effects of the anti-stress (oxytocin) system become more prominent, moderating lifelong health trajectories. There is clear evidence that HPA axis activity during this time is dependent on the balance between the HPA axis and the oxytocin system, the latter being reinforced by specific somatosensory inputs, and this has long-term consequences for stress reactivity.
To investigate the response to antidepressants while controlling for sex, which has been controversial, 92 outpatient males and females with major depressive disorder were assigned to sertraline (100 mg/day) or citalopram (40 mg/day) in two strata and were assessed using Hamilton depression rating scale (HDRS) scores and brain-derived neurotrophic factor (BDNF), interleukin (IL)-6 and cortisol serum levels in this 8-week, randomized, parallel-group, double-blind clinical trial. Data of 40 sertraline and 40 citalopram recipients with equal representation of males and females assigned to each medication were analyzed, while their baseline characteristics were not statistically different ( P > 0.05). There were no significant differences between sertraline and citalopram recipients in outcome changes ( P > 0.05), all of which indicated improvement, but a significant time-treatment-sex interaction effect in BDNF levels was observed ( P = 0.035). Regarding this, subgroup analyses illustrated a significantly greater increase in male BDNF levels following sertraline treatment ( P = 0.020) with a moderate to large effect size (Cohen’s d = 0.76 and ). Significant associations were observed between percentage changes in IL-6 levels and BDNF levels in sertraline recipients ( P = 0.033) and HDRS scores in citalopram recipients ( P < 0.001). Sex was an effect modifier in BDNF alterations following sertraline and citalopram administration. Further large-scale, high-quality, long-term studies are recommended.
The presence of resident microbial species in the human gastrointestinal tract has been known for a long time. However, only recently have they been recognized as tremendous regulators of overall host pathophysiology. Interestingly, the central nervous system (CNS) features as a key target of the gut microflora. Recent studies indicate that the bidirectional interactions of the microbiota-gut-brain axis play critical roles in influencing a plethora of neuroendocrine and neuroinflammatory mediators, with huge implications for neurotransmitter physiology at the levels of enteric, autonomous, and central nervous systems. This chapter deals with the discussion of the pathophysiological roles of the resident microflora in the developing and adult brains, focusing on the two relevant aspects of blood-brain barrier development and adult hippocampal neurogenesis. Further, dysbiosis of the gut microbiome as a pathogenic factor for the development of CNS disorders (e.g., multiple sclerosis, Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and stroke) is detailed. We also discuss the possibilities of harnessing the alterations in the gut microbial species for diagnostic, prognostic, and therapeutic purposes for these diseases. Lastly, the implications of the microbiota-gut-brain axis for promoting longevity and healthy ageing are illustrated.
Investigating acute stress responses is crucial to understanding the underlying mechanisms of stress. Current stress assessment methods include self-reports that can be biased and biomarkers that are often based on complex laboratory procedures. A promising additional modality for stress assessment might be the observation of body movements, which are affected by negative emotions and threatening situations. In this paper, we investigated the relationship between acute psychosocial stress induction and body posture and movements. We collected motion data from N = 59 individuals over two studies ( Pilot Study : N = 20, Main Study : N = 39) using inertial measurement unit (IMU)-based motion capture suits. In both studies, individuals underwent the Trier Social Stress Test (TSST) and a stress-free control condition (friendly-TSST; f-TSST) in randomized order. Our results show that acute stress induction leads to a reproducible freezing behavior, characterized by less overall motion as well as more and longer periods of no movement. Based on these data, we trained machine learning pipelines to detect acute stress solely from movement information, achieving an accuracy of $${75.0 \pm 17.7}{\%}$$ 75.0 ± 17.7 % ( Pilot Study ) and $${73.4 \pm 7.7}{\%}$$ 73.4 ± 7.7 % ( Main Study ). This, for the first time, suggests that body posture and movements can be used to detect whether individuals are exposed to acute psychosocial stress. While more studies are needed to further validate our approach, we are convinced that motion information can be a valuable extension to the existing biomarkers and can help to obtain a more holistic picture of the human stress response. Our work is the first to systematically explore the use of full-body body posture and movement to gain novel insights into the human stress response and its effects on the body and mind.
This study investigates the effectiveness of the TRUST intervention, delivered through Information and Communication Technology (ICT), in addressing trauma and enhancing resilience among Eritrean refugees in impoverished camps. The research aims to explore whether the comprehensive TRUST program, compared to a shorter psycho-education session, can reduce traumatic stress levels and improve social and economic resilience and social capital, indicating a reduction in collective trauma. Ethical approval was obtained, and participants were randomly assigned to intervention groups. Livelihood support availability was assessed, and psychometric tests were administered before and after the intervention. Results indicate a significant decrease in traumatic stress levels and improvements in social and economic resilience among participants receiving the full TRUST intervention. Interestingly, the availability of livelihood support did not significantly impact trauma levels or associated improvements. Challenges in delivering therapy via ICT, such as connectivity issues, were identified. This study underscores the potential of ICT-enabled interventions in addressing mental health challenges in resource-constrained environments but highlights the importance of addressing connectivity issues for effective implementation.
Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.
Preeclampsia (PE) is a multisystem disorder characterized by elevated blood pressure in the mother, typically occurring after 20 weeks of gestation and posing risks to both maternal and fetal health. PE causes placental changes that can affect the fetus, particularly neurodevelopment. Its key pathophysiological mechanisms encompass hypoxia, vascular and angiogenic dysregulation, inflammation, neuronal and glial alterations, and disruptions in neuronal signaling. Animal models indicate that PE is correlated with neurodevelopmental alterations and cognitive dysfunctions in offspring and in humans, an association between PE and conditions such as cerebral palsy, autism spectrum disorder, attention deficit hyperactivity disorder, and sexual dimorphism has been observed. Considering the relevance for mothers and children, we conducted a narrative literature review to describe the relationships between the pathophysiological mechanisms behind neurodevelopmental alterations in the offspring of PE mothers, along with their potential consequences. Furthermore, we emphasize aspects pertinent to the prevention/treatment of PE in pregnant mothers and alterations observed in their offspring. The present narrative review offers a current, complete, and exhaustive analysis of (i) the pathophysiological mechanisms that can affect neurodevelopment in the children of PE mothers, (ii) the relationship between PE and neurological alterations in offspring, and (iii) the prevention/treatment of PE.
This review aims to argue how using probiotics can improve anxiety and depressive behaviour without adverse effects, also exploring the impact of postbiotics on it. Specifically, probiotics have drawn more attention as effective alternative treatments, considering the rising cost of antidepressant and anti-anxiety drugs and the high risk of side effects. Depression and anxiety disorders are among the most common mental illnesses in the world's population, characterised by low mood, poor general interest, and cognitive or motor dysfunction. Thus, this study analysed published literature on anxiety, depression, and probiotic supplementation from PubMed and Scopus, focusing on the last twenty years. This study focused on the effect of probiotics on mental health as they have drawn more attention because of their extensive clinical applications and positive impact on various diseases. Numerous studies have demonstrated how the gut microbiota might be critical for mood regulation and how probiotics can affect host health by regulating the gut-brain axis. By comparing the different works analysed, it was possible to identify a strategy by which they are selected and employed and, at the same time, to assess how the effect of probiotics can be optimised using postbiotics, an innovation to improve mental well-being in humans.
The key organ of the peripheral endocrine system, the thyroid gland, shows the ability to adapt and restructure at diff erent levels of structural and cellular organization under the infl uence of various factors. The aim of the study was to determine morphometric changes in the parameters of the structural components of the thyroid gland. The experiment was modeled on 42 male laboratory mature white rats. The burn was modeled with copper plates heated in water at a temperature of 97-100 °C. The size of the aff ected area was 20 % of the animal’s body area, which, according to the current classifi cation, corresponds to a seconddegree burn. Changes in various parameters were studied by morphometric analysis of the obtained histologic sections. Statistical processing of digital data was carried out using the software «Excel» and «STATISTICA» 10.0 using parametric and nonparametric methods of data evaluation. Morphometrically, it was found that the organ contains follicles of three types – large, medium and small, and their quantitative ratio is 1.4: 4,7: 3,9. It was found that the average value of the area of a small follicle is (2342.5498.43) μm2, medium – (3722.53130.44) μm2, large – (5733.77203.67) μm2. The average value of thyrocyte height is (11.430.41) μm. The follicular- colloid index of the thyroid gland of intact animals is the highest for small follicles and is 1.940.08, for medium follicles – 1.81 0.04 and for large follicles – 1.730.05. The average value of the colloid accumulation index for small follicles is the lowest and is 2.600.12, for medium follicles – 4.18 0.19, and for large follicles – 6.270.29. At the light- optical level, on day 7 of the experiment, an increase in the number (1.58 times (p<0.001) compared to the intact index) of large follicles was noted, which are located mainly on the periphery of the lobules and fi lled with a compacted colloid. A decrease in thyrocyte height (1.29 times (p<0.001) compared to the normal value), a signifi cant decrease in the follicular- colloid index and an increase in the colloid accumulation index detected in the early toxemia stage indicate a decrease in functional activity in the organ, disruption of adaptive processes in it and the onset of destructive changes. At the later stages of burn injury (14 and 21 days of the experiment), against the background of a statistically signifi cant (p<0.001) increase in endogenous intoxication, there is a development of deep destructive changes in thyrocytes, organ vessels, proliferation of connective tissue layers, impaired synthesis and secretion of hormones. These conditions are manifested by the dominance of large, overstretched follicles in the parenchyma of the thyroid gland, lined with fl at, degenerating thyrocytes, the height of which at day 21 is 3.31 times signifi cantly (p<0.001) lower than the intact value; a statistically signifi cant decrease in the follicular- colloid index; a signifi cant increase in the colloid accumulation index, as well as a signifi cant deviation from the normal level of pituitary- thyroid system homones, which indicates organ hypofunction.
Hücre Fizyolojisi Damla AYKORA Kan Fizyolojisi Ferhat ŞİRİNYILDIZ Kas Fizyolojisi Özlem BARUTÇU Kardiyovasküler Sistem Fizyolojisi Seda UĞRAŞ HARMAN Solunum Sistemi Fizyolojisi Mehmet ÖZ Boşaltım Sistemi Fizyolojisi Seda UĞRAŞ HARMAN Endokrin Sistem Fizyolojisi Ferhat ŞİRİNYILDIZ Üreme Sistemi Fizyolojisi Burcu KÖKSAL Sindirim Sistemi Fizyolojisi İlknur BİRSEN Duyu Fizyolojisi Elif Ezgi GÜREL Sinir Sistemi Fizyolojisi Gül Şahika GÖKDEMİR
Objective.
—This article defines stress and related concepts and reviews their historical development. The notion of a stress system as the effector of the stress syndrome is suggested, and its physiologic and pathophysiologic manifestations are described. A new perspective on human disease states associated with dysregulation of the stress system is provided.
We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin
on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral
administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid
by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response
studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this
dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of
two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited
a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and
defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress.
Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic,
and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological
stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive,
and cardiovascular disorders associated with CRH system hyperactivity.
This article defines stress and related concepts and reviews their historical development. The notion of a stress system as the effector of the stress syndrome is suggested, and its physiologic and pathophysiologic manifestations are described. A new perspective on human disease states associated with dysregulation of the stress system is provided.
Published original articles from human and animal studies and selected reviews. Literature was surveyed utilizing MEDLINE and the Index Medicus.
Original articles from the basic science and human literature consisted entirely of controlled studies based on verified methodologies and, with the exception of the most recent studies, replicated by more than one laboratory. Many of the basic science and clinical studies had been conducted in our own laboratories and clinical research units. Reviews cited were written by acknowledged leaders in the fields of neurobiology, endocrinology, and behavior.
Independent extraction and cross-referencing by the authors.
Stress and related concepts can be traced as far back as written science and medicine. The stress system coordinates the generalized stress response, which takes place when a stressor of any kind exceeds a threshold. The main components of the stress system are the corticotropin-releasing hormone and locus ceruleus-norepinephrine/autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival. There has been an exponential increase in knowledge regarding the interactions among the components of the stress system and between the stress system and other brain elements involved in the regulation of emotion, cognitive function, and behavior, as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of stress system dysfunction, characterized by sustained hyperactivity and/or hypoactivity, to various pathophysiologic states that cut across the traditional boundaries of medical disciplines. These include a range of psychiatric, endocrine, and inflammatory disorders and/or susceptibility to such disorders.
We hope that knowledge from apparently disparate fields of science and medicine integrated into a working theoretical framework will allow generation and testing of new hypotheses on the pathophysiology and diagnosis of, and therapy for, a variety of human illnesses reflecting systematic alterations in the principal effectors of the generalized stress response. We predict that pharmacologic agents capable of altering the central apparatus that governs the stress response will be useful in the treatment of many of these illnesses.
To examine whether the hypothalamic corticotropin-releasing hormone (CRH) neuron is regulated by CRH, by products of the proopiomelanocortin (POMC) gene, and/or by glucocorticoids, we used a rat hypothalamic organ culture system in which rat CRH secretion from single explanted hypothalami was evaluated by an RIA (iCRH) specific for rat CRH. The effects of graded concentrations of ovine CRH (oCRH), adrenocorticotropin hormone (ACTH), beta-endorphin (beta-EP), alpha-melanocyte-stimulating hormone (alpha-MSH), corticotropin-like intermediate lobe peptide (CLIP), ovine beta-lipotropin (ovine beta-LPH), and dexamethasone (DEX) upon unstimulated and serotonin- (5HT), acetylcholine- (ACh), and norepinephrine-(NE) stimulated CRH secretion were determined. oCRH and DEX inhibited unstimulated iCRH secretion with ID50 at the 10(-8) M range. ACTH had no detectable suppressive effect at 10(-8) M. oCRH, ACTH, and DEX inhibited 5HT-, ACh-, and NE-stimulated iCRH secretion in a dose-dependent fashion. beta-EP, alpha-MSH, and CLIP also inhibited 5HT-induced iCRH secretion. Of the latter peptides, the strongest inhibitor was beta-EP and the weakest was CLIP. Ovine beta-LPH had only a weak inhibitory effect on 5HT-induced iCRH secretion. Generally, the concentrations required for 50% suppression of neurotransmitter-stimulated iCRH secretion were significantly lower than those required for a similar suppression of unstimulated iCRH secretion. In conclusion, these data suggest the presence of multiple negative feedback loops involved in the regulation of the hypothalamic CRH neuron: an ultrashort CRH-mediated loop, a short, hypothalamic POMC-derived peptide loop, and a long, glucocorticoid-mediated negative feedback loop. The potency of these negative feedback loops may be determined by the state of activation of the CRH neuron.
Celsus described four of the five cardinal signs of inflammation 2000 years ago, and Eustachio discovered the adrenal glands almost 500 years ago, but not until 1936 did Selye note that in rats exposed to stressors, the adrenal glands were enlarged, and the thymus and lymph nodes shrunken.1–3 Cortisone, the active principle of the adrenal glands, was isolated by Kendall and Reichstein in the late 1940s and shown to suppress immune organs. These scientists, along with Hench, received the Nobel Prize in Physiology and Medicine, after Hench and colleagues showed that cortisone could ameliorate rheumatoid arthritis.4,5 In recent . . .
Glucocorticoids are potent immunosuppressants which work in part by inhibiting cytokine gene transcription. We show here that NF-kappa B, an important regulator of numerous cytokine genes, is functionally inhibited by the synthetic glucocorticoid dexamethasone (DEX). In transfection experiments, DEX treatment in the presence of cotransfected glucocorticoid receptor (GR) inhibits NF-kappa B p65-mediated gene expression and p65 inhibits GR activation of a glucocorticoid response element. Evidence is presented for a direct interaction between GR and the NF-kappa B subunits p65 and p50. In addition, we demonstrate that the ability of p65, p50, and c-rel subunits to bind DNA is inhibited by DEX and GR. In HeLa cells, DEX activation of endogenous GR is sufficient to block tumor necrosis factor alpha or interleukin 1 activation of NF-kappa B at the levels of both DNA binding and transcriptional activation. DEX treatment of HeLa cells also results in a significant loss of nuclear p65 and a slight increase in cytoplasmic p65. These data reveal a second mechanism by which NF-kappa B activity may be regulated by DEX. We also report that RU486 treatment of wild-type GR and DEX treatment of a transactivation mutant of GR each can significantly inhibit p65 activity. In addition, we found that the zinc finger domain of GR is necessary for the inhibition of p65. This domain is also required for GR repression of AP-1. Surprisingly, while both AP-1 and NF-kappa B can be inhibited by activated GR, synergistic NF-kappa B/AP-1 activity is largely unaffected. These data suggest that NF-kappa B, AP-1, and GR interact in a complex regulatory network to modulate gene expression and that cross-coupling of NF-kappa B and GR plays an important role in glucocorticoid-mediated repression of cytokine transcription.
Corticotropin-releasing hormone (CRH) plays major roles in coordination of the stress response and regulation of the immune/inflammatory reaction, two important functions associated with sexual dimorphism. Two overlapping segments of the 5' flanking region of the human (h) CRH gene, the proximal 0.9 kb (containing two perfect half-palindromic estrogen-responsive elements [EREs]) and the 2.4 kb (including the former and containing two additional perfect half-palindromic EREs), were examined for their ability to confer estrogen-mediated transcriptional enhancement to a homologous or heterologous promoter. The level of estrogen-induced transactivation by the 0.9- and 2.4-kb segments was determined by chloramphenicol acetyltransferase analysis in CV-1 cells cotransfected with estrogen receptor (ER) cDNA expression plasmids, and found to be respectively approximately 10% and 20% of that of the strongly estrogen-responsive Xenopus vitellogenin A2 enhancer. Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. These findings may constitute the basis of sexual dimorphism in the expression of the CRH gene in the central nervous system and periphery, and might shed light in existing gender differences in stress response and immune regulation.
Inflammatory cytokines have metabolic actions that probably contribute to the general adaptation of the organism during infectious or inflammatory stress. To examine the effects of interleukin 6 (IL-6), the main circulating cytokine, on glucose metabolism in man, we performed dose-response studies of recombinant human IL-6 in normal volunteers. Increasing single doses of IL-6 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/Kg BW) were injected sc in 15 healthy male volunteers (3 in each dose) after a 12-h fast. All IL-6 doses were tolerated well and produced no significant adverse effects. We measured the circulating levels of glucose, insulin, C-peptide, and glucagon at baseline and half-hourly over 4 h after the IL-6 injection. Mean peak plasma levels of IL-6 were achieved between 120 and 240 min and were 8, 22, 65, 290, and 4050 pg/mL, respectively, for the 5 doses. After administration of the 2 smaller IL-6 doses, we observed no significant changes in plasma glucose levels, which, because of continued fasting, decreased slightly over time. By 60 min after the 3 higher IL-6 doses, however, the decline in fasting blood glucose was arrested, and glucose levels increased in a dose-dependent fashion. The concurrent levels of plasma insulin and C-peptide were not affected by any IL-6 dose. In contrast, IL-6 caused significant increases in plasma glucagon levels, which peaked between 120 and 150 min after the IL-6 injection. In conclusion, sc IL-6 administration induced dose-dependent increases in fasting blood glucose, probably by stimulating glucagon release and other counteregulatory hormones and/or by inducing peripheral resistance to insulin action.
This review examines the central actions exerted by corticosteroids that are mediated by mineralocorticoid receptors (MRs or Type 1) and glucocorticoid receptocs (GRs or Type 2) in the brain. The leitmotiv is that these MR- and GR-mediated effects of the steroid hormones are of critical importance for homeostatic control. MRs have aldosterone (ALDO)-selective properties in some nerve cells and apparent corticosterone (B)-selective properties in others, notably the limbic neurons. Compartmentalization of the MR subtypes hinges on activity of 11β-hydroxysteroid dehydrogenase and corticosteroid-binding globulin. B also binds to GRs, but with 10-fold lower affinity. GR density is high in brain regions involved in organization of the stress response. GR-mediated corticosteroid effects inhibit stress-induced pituitary proopiomelanocortin and hypothalamic corticotropin-releasing hormone and vasopressin synthesis, but facilitate activation and sensitization of ascending aminergic neurons. In hippocampal CA1 neurons, co-localized MRs and GRs coordinately and differentially mediate corticosteroid control of ion regulation and transmitter responsiveness. MRs are involved in maintenance of excitability, while GRs suppress excitability, which is transiently raised by excitatory transmitters. At the neuroendocrine level, B sets the threshold for the stress response system via binding to MRs. Blockade of MRs enhances basal and stress-induced hypothalamo-pituitary-adrenal (HPA) activity. Stress- and circadian-induced episodic occupancy by B of GRs in hippocampus attenuates MR-mediated limbic inhibition. In hypothalamus, B blocks via binding to GRs the communication of the HPA axis. At the behavioral level, the ALDO-selective MRs mediate specific effects on salt hunger and functions associated with sodium homeostasis such as central cardiovascular control. Limbic MRs seem primarily concerned with B effects on information handling and the organization of behavioral strategies. GRs mediate steroid effects on fear- and food-motivated behavior and information storage. GR-mediated effects on behavior may persist for weeks in adulthood and appear permanent during development. High glucocorticoids decrease hippocampal GR and increase MR capacity, while mineralocorticoids down-regulate both receptor types. Animals with an increased relative amount of limbic MRs over GRs show reduced emotional and adrenocortical reactivity and a decreased ability to organize behavior with the help of external stimuli. Deviations of an idiosyncratic MR/GR balance are proposed to alter individual-specific susceptibility to stress and © 1991 Raven Press perhaps to stress-related brain diseases. The findings place Selye's "pendulum hypothesis" on mineralocorticoid and glucocorticoid action in the perspective of co-localized MRs and GRs mediating coordinate and differential effects of B on regulation of cellular homeostasis and behavioral adaptation.
A peptide with high potency and intrinsic activity for stimulating the
secretion of corticotropin-like and β -endorphin-like
immunoactivities by cultured anterior pituitary cells has been purified
from ovine hypothalamic extracts. The primary structure of this
41-residue corticotropin- and β -endorphin-releasing factor has
been determined to be:
H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-
Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-
Lys-Leu-Leu-Asp-Ile-Ala-NH2 The synthetic peptide is active
in vitro and in vivo.
Interleukin-6 (IL-6), the main circulating cytokine, is putatively a major mediator of the effects of the immune system on several endocrine axes and intermediate metabolism. We performed dose-response studies of recombinant human IL·6 on pituitary hormone secretion in 15 healthy male volunteers, using 5 single, escalating subcutaneous doses of IL-6 (0.1, 0.3, 1.0, 3.0 and 10.0 μg/kg body weight), each in 3 volunteers. We measured resting metabolic rate (RMR) with indirect calorimetry and plasma anterior pituitary hormones and vasopressin (AVP) at baseline and half-hourly over 4 h after the injection. All doses examined were tolerated well and produced no significant adverse effects. Dose-dependent RMR increases were observed in response to the 3.0- and 10.0-μg/kg doses of IL-6, beginning at 60 min and slowly peaking between 180 and 240 min. Plasma adrenocorticotropic-hormone concentrations increased dramatically and dose-dependently in all the patients who received the 3.0- and 10.0-μg/kg doses of IL-6, respectively, peaking to 150 and 255 pg/ml at 60 min, and slowly returning to normal by 4 h. Corresponding plasma cortisol levels peaked dose-dependently between 90 and 150 min, but remained elevated throughout the sampling period. In contrast, the growth hormone (GH) dose-response was bell-shaped, with maximum (approximately 100-fold) stimulation achieved by 3.0 μg/kg IL-6. Prolactin (PRL) showed a similar but less pronounced response pattern. Thyroid-stimulating hormone (TSH) dose-dependently and progressively decreased over the 240 min, while gonadotropins showed no clear-cut changes. In conclusion, subcutaneous IL-6 administration induced synchronized dose-dependent increases in the RMR and hypothalamic-pituitary-adrenal axis activity, suggesting that hypothalamic corticotropin-releasing hormone may mediate both of these functions in humans. IL-6 also acutely stimulated GH and PRL secretion and suppressed TSH secretion. The dose of 3.0 μg/kg could be used safely in the study of patients with disturbances of the hypothalamic-pituitary unit or of thermogenesis.
Studies were undertaken to characterize the secretion of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) into the hypophysial-portal circulation of the conscious sheep. In addition, we examined the temporal relationship between the secretion of these two hypothalamic peptides and the secretion of three pro-opiomelanocortin peptides – adrenocorticotropic hormone (ACTH), ir-β-endorphin, and ir-α-melanocyte-stimulating hormone – and cortisol and determined the effects of an audiovisual emotional stimulus and insulin-induced hypoglycemia on the entire hypothalamic-pituitary-adrenal axis. In the basal state, the secretion of CRF, AVP, the three pro-opiomelanocortin peptides, and cortisol was pulsatile in nature, and three CRF and AVP pulse patterns were observed: a concordant increase in CRF and AVP, an isolated rise in CRF, and an isolated increase in AVP. In 4 of the 5 animals, a 3-min audiovisual stress (barking dog) rapidly increased the plasma levels of all the measured substances, although the magnitude and duration of the effect differed markedly between the animals. Insulin-induced hypoglycemia markedly increased AVP and, to a lesser extent, CRF concentrations in portal plasma and thereby altered the CRF:AVP molar ratio. Although pituitary-adrenal activation was closely correlated with the increased hypothalamic activity, a strict 1:1 concordance between CRF/AVP secretion and ACTH secretion was not seen. The anesthetic ketamine selectively increased portal AVP concentrations to levels which exceeded those attained during hypoglycemia and rapidly activated the pituitary-adrenal axis. We conclude the following: (1) CRF and AVP are secreted by the hypothalamus in a pulsatile fashion; (2) ACTH secretion can be stimulated by increases in either CRF or AVP; (3) the absence of a strict 1:1 concordance between hypothalamic CRF/AVP release and pituitary ACTH secretion during stress may be partly due to the release of additional hypothalamic ACTH secretagogues; (4) the ability of both audiovisual stimuli and insulin-induced hypoglycemia to augment CRF and AVP secretion indicates that the paraventricular hypothalamus may be activated by a variety of neural inputs, and (5) the marked alteration of the CRF:AVP molar ratio during stress suggests that AVP may be an important ACTH secretagogue in vivo in the sheep.
Corticotropin-releasing hormone (CRH) influences the immune system indirectly, through activation of the hypothalamic-pituitary-adrenal axis and sympathetic system, and directly, through local modulatory actions of peripheral (immune) CRH. We recently demonstrated that catecholamines and histamine potently inhibited interleukin (IL)-12 and stimulated IL-10, whereas glucocorticoids suppressed IL-12, but did not affect IL-10 production ex vivo. Thus, both glucocorticoids and catecholamines, the end products of the stress system, and histamine, a product of activated mast cells, may selectively suppress cellular immunity and favor humoral immune responses. We localized immunoreactive CRH in experimental carrageenin-induced aseptic inflammation and, in humans, in inflamed tissues from patients with several autoimmune diseases. In addition, we demonstrated that CRH activated mast cells via a CRH receptor type 1-dependent mechanism, leading to release of histamine and hence vasodilatation and increased vascular permeability. Thus, activation of the stress system, through direct and indirect effects of CRH, may influence the susceptibility of an individual to certain autoimmune, allergic, infectious or neoplastic diseases. Antalarmin, a novel nonpeptide CRH antagonist, prevented several proinflammatory effects of CRH, thus revealing its therapeutic potential in some forms of inflammation.
To determine the integrity of the hypothalamic-pituitary-adrenal (HPA) axis responses to immune/inflammatory stimuli in patients with rheumatoid arthritis (RA).
Diurnal secretion of cortisol and the cytokine and cortisol responses to surgery were studied in subjects with active RA, in subjects with chronic osteomyelitis (OM), and in subjects with noninflammatory arthritis, who served as controls.
Patients with RA had a defective HPA response, as evidenced by a diurnal cortisol rhythm of secretion which was at the lower limit of normal in contrast to those with OM, and a failure to increase cortisol secretion following surgery, despite high levels of interleukin-1 beta (IL-1 beta) and IL-6. The corticotropin-releasing hormone stimulation test in the RA patients showed normal results, thus suggesting a hypothalamic defect, but normal pituitary and adrenal function.
These findings suggest that RA patients have an abnormality of the HPA axis response to immune/inflammatory stimuli which may reside in the hypothalamus. This hypothalamic abnormality may be an additional, and hitherto unrecognized, factor in the pathogenesis of RA.
This article is an up-to-date review of the impact that the discovery of corticotropin-releasing hormone (CRH) has had on basic science and clinical medicine. It discusses hypothalamic CRH, placental CRH, immune CRH, and hypothalamic and immune CRH. Clinical studies in normal and disease states and synthesis and future directions also are presented.
This article reviews the mechanisms believed to mediate stress-induced inhibition of reproductive functions and the anatomical sites at which these effects take place. Particular emphasis is placed on the potential modulating role of hormones or neurotransmitters released during stress. At the level of the gonads, adrenal corticoids, pro-opiomelanocortin (POMC)-like peptides, and corticotropin-releasing factor (CRF) are reported to interfere with the stimulatory action of gonadotropins on sex steroid-producing cells. Increased circulating corticosteroid levels may also decrease pituitary responsiveness to GnRH. There is, however, increasing evidence that these mechanisms are primarily involved in mediating the effects of prolonged stress, but not those of an acute stimulus. In contrast, a variety of hormones or neurotransmitters, including CRF, POMC peptides, and biogenic amines act within the brain to mediate the inhibitory influence of both acute and prolonged stresses on reproductive function.
It is widely accepted that chronic administration of corticoids in man inhibits the GH response to all of the stimuli tested so far. To study the action of corticoids administered acutely, several dexamethasone challenge tests were performed, after which GH levels were measured for 7 h. In eight volunteers, administration of 4 mg dexamethasone (Dex), iv, induced a clear-cut GH release compared with saline administration. The secretion followed an unusual pattern; basal GH levels (1.5 +/- 0.1 micrograms/L) started rising 2 h after Dex injection, reaching a peak of 17.5 +/- 4.4 micrograms/L after 3 or 3.5 h. Peak levels were maintained until 5 h post-Dex and decreased thereafter. Similar data were obtained when Dex was administered to five volunteers at the dose of 8 mg, orally, with a 30-min delay of the GH peak (19.6 +/- 7.9 micrograms/L). To study whether there was a cholinergic input responsible for the Dex action, another group of eight volunteers underwent three Dex tests (4 mg, iv) on three occasions, followed 90 min later by the administration of placebo (control), atropine (0.5 mg, iv), or pyridostigmine (120 mg, orally). The Dex-induced GH peak (20.8 +/- 5.2 micrograms/L) was not significantly increased by pyridostigmine (cholinergic agonist) treatment (24.2 +/- 4.0 micrograms/L). The blockade of muscarinic receptors by atropine induced a delay in the Dex-induced secretory peak, which appeared at 5 h. However, the Dex-atropine GH peak (14.9 +/- 4.1 micrograms/L) was not different from the Dex-placebo one. In conclusion, Dex alone is able to induce a clear-cut GH secretion in man. The stimulus followed a peculiar time pattern, with peaks levels attained 3 h after either iv or oral administration.
In humans, corticoids suppress growth and growth hormone (GH) secretion elicited by a variety of stimuli, while in the rat they potentiate both in vivo and in vitro GH release. To further study this problem, growth-hormone-releasing hormone (GHRH) tests were performed in 6 nonobese Cushing's syndrome patients and 6 controls. The normal GHRH-induced GH secretion was completely abolished in the Cushing's syndrome group. To study the action of shorter corticoid exposures, 34 volunteers were subjected to four tests each: placebo treatment (control); dexamethasone (Dex) administration 4 mg i.v., 3 h before; Dex 8 mg p.o., 12 h before, and Dex 22 mg p.o. over the 2 days before the pituitary challenge that was always administered at 0 min (12.00 h). In the first test (n = 9), GHRH (1 microgram/kg i.v.) induced a GH peak of 14.5 +/- 3.8 ng/ml (control) that was potentiated by Dex 4 mg i.v. administered 3 h before (26.4 +/- 6.8 ng/ml). On the contrary, longer Dex treatments suppress GHRH-induced GH values (6.0 +/- 1.1 ng/ml after Dex 8 mg and 1.8 +/- 0.3 ng/ml after Dex 22 mg). Clonidine administration 300 micrograms p.o. (n = 7) increased GH secretion with an area under the secretory curve (AUC) of 1,274 +/- 236 that was potentiated by Dex 4 mg i.v. given 3 h before clonidine (2,380 +/- 489) and reduced by Dex 8 mg, the reduction being significant only after 22 mg Dex (595 +/- 47).(ABSTRACT TRUNCATED AT 250 WORDS)
Thyrotrophin (TSH) secretion was studied in 63 patients with Cushing's syndrome (53 patients with pituitary dependent Cushing's disease, eight with adrenocortical tumours, and two with the ectopic ACTH syndrome). Prior to treatment, TSH response to 200 micrograms of TRH intravenously was significantly decreased compared to controls; TSH response was 'flat' (increment less than 2 mU/l) in 34 patients (54%). Patients with a flat response to TRH had significantly higher morning and midnight cortisol levels than patients with a TSH response of 2 mU/l and more; this was not due to differences in serum thyroid hormone levels. Basal TSH, TSH increment after TRH, and stimulated TSH value, but not serum triiodothyronine, were correlated with cortisol measurements (0800 h serum cortisol, midnight cortisol, and urinary free corticoid excretion). After exclusion of 40 patients with additional disease (severe systemic disease, diabetes mellitus, or goitre), cortisol-TSH correlations were even more pronounced (r = -0.73 for midnight cortisol and stimulated TSH levels), while in the patients with additional complications, these correlations were slight or absent. Successful treatment in 20 patients was associated with a rise in thyroid hormone levels and the TSH response to TRH. These results indicate that (1) the corticoid excess but not serum T3 is the principal factor regulating TSH secretion in Cushing's syndrome, (2) a totally flat response to TRH is rare, and (3) TSH suppression and lower than normal serum thyroid hormone levels are reversible after treatment. Since factors like severe systemic disease, diabetes mellitus and goitre also affect TSH secretion, they tend to obscure the statistically significant correlations between cortisol excess and TSH secretion.
Patterns of plasma ACTH and cortisol concentrations were studied in 10 healthy subjects (five male, five female in the early follicular phase, overall age range 21-32 years) by sampling through an indwelling cannula every 15 min for 24 h. The subjects were in hospital, ambulant, and taking normal meals. Plasma ACTH was measured by a two-site immunoradiometric assay with a detection limit of 3.9 ng/l (0.9 pmol/l). Pulses were identified by the method of Clayton et al. (1987) using stringent criteria to minimize false positive peaks. All subjects showed a circadian rhythm of ACTH, the acrophase occurring between 0615 and 0920 h in all but one subject and the mesor value was between 9.2 and 18.6 ng/l (2.0 and 4.1 pmol/l). There were significantly fewer pulses between 1800 and 2400 h compared with the other three 6-h periods. The pattern of ACTH differed between males and females in several respects: more pulses (18 vs 10), greater mean peak amplitude (16.8 vs 10.3 ng/l), greater area under the 24-h profile (350.9 vs 206.6 ng/l h) and higher mean level (14.7 vs 8.6 ng/l) in the males. In contrast, the cortisol pattern did not show statistically different sex differences. The sex differences suggest greater sensitivity to, or availability of, ACTH to the female adrenal cortex, or different set points in cortisol feedback.
Excerpt
The classical perspective of the adrenal gland has, in general, treated the cortex and medulla as functionally independent tissues which, by chance, are located together. Recent data challenge this outlook, and there is now evidence of regulatory mechanisms which are common to both the cortex and the medulla. There is, additionally, more evidence that the products of each of these tissues may influence the function of the other.
In mammals the arrangement of the adrenal gland is such that the adrenal cortex forms the outer part of the gland and totally encloses the medulla. Indeed, a close anatomical relationship, between the morphologically and functionally distinct steroid-secreting tissue and chromaffin tissue in the adrenal gland, is seen in most vertebrate groups. Why should these embryologically unrelated tissues be located together, and what is their functional link?
There is a wealth of experimental evidence to support the contention that these tissues have
Corticotropin-releasing factor (CRF) at doses of 10(-12)-10(-8) M significantly stimulated the release of beta-endorphin and dynorphin from superfused rat hypothalamic slices. These effects were shown to be mediated by the CRF receptor since they were antagonized by the CRF receptor antagonist alpha-helical CRF9-41 (10(-6) M). The two opioid peptides showed different time courses of response and in the case of beta-endorphin, an attenuation of the response upon continued exposure to CRF was observed.
Vasopressin (arginine vasopressin, AVP) is present in two types of nerve fibres in the median eminence (ME). First, it is found in nerve terminals that originate in the parvicellular neurones of the hypothalamic paraventricular nucleus (PVN) and abut on the pericapillary space surrounding the fenestrated capillaries of the primary pituitary portal plexus in the external zone (EZ) of the ME. These neurones also synthesize corticotropin-releasing factor (CRF), which acts synergetically with vasopressin to stimulate release of adrenocorticotropin (ACTH) from the pituitary gland (see ref. 7). Second, vasopressinergic axons of the magnocellular neurosecretory system pass through the internal zone (IZ) of the ME to terminate in the neurohaemal contact zone of the neurohypophysis. The involvement of vasopressinergic magnocellular neurones in the control of ACTH secretion is much debated. Of particular interest in this context is the origin of the vasopressin found in pituitary portal blood. Although it has been demonstrated that vasopressin and CRF are present in the same neurosecretory granules of EZ fibres, parallel determinations of vasopressin and CRF in pituitary portal blood have shown alterations of the concentration of vasopressin without a concomitant change in that of CRF. Such a dissociation suggests that either differential release of vasopressin and CRF can occur from a single population of nerve endings, or there are fibres in the pituitary-stalk ME which release vasopressin but not CRF. Here we present evidence for the latter. Our results indicate that stimuli causing depolarization of the axonal membrane in vitro elicit release of vasopressin from nerve fibres in the external and internal zones of the ME.
Thousands of studies have been conducted of the functioning of the many neurotransmitter systems in order to explore the biologic basis of major depressive disorder. Instead of reviewing this literature exhaustively, we have attempted to propose a model that accommodates the clinical observation that chronic stress early in life in vulnerable persons predisposes them to major depression with contemporary observations of the potential consequences of repeated central nervous system exposure to effectors of the stress response. This model accords with current clinical judgment that major depression is best treated with a combination of psychopharmacologic agents and psychotherapy. Accordingly, whereas psychopharmacologic intervention may be required to resolve an active episode of major depression and to prevent recurrences, psychotherapy may be equally important to lessen the burden of stress imposed by intense inner conflict and counterproductive defenses.
In this review, the emerging functional roles of the brain angiotensin system have been considered. The major effects of Ang II can be classified into three groups, which imply three possible functions: The first, and largest, group is actions associated with the regulation of body fluid volume in response to hypovolemia. These include thirst, blood pressure increase, vasopressin release, sodium appetite and excretion, and ACTH and aldosterone release. This function alone has important implications for the control of blood pressure and the disease of hypertension. Another possible function is a role for angiotensin in the activity of gonadotropic hormone releasing hormones and pituitary hormones during the reproductive cycle and pregnancy. A third group of functions is the synaptic, neurotransmitter interactions of Ang II with catecholamines, serotonin, prostaglandins, and other peptides, not all of which could be reviewed here due to space limitations. This interaction is significant for all functions mentioned and leads to alterations in motivation (thirst, pain), memory (and possibly learning), and motor control. The amount of data available, however, is so limited that to claim angiotensin plays any major role in the latter functions would be premature. Throughout this review, we compared the central and peripheral effects of Ang II. We suggest that normally, a blood-CVO barrier prevents diffusion of peripheral Ang II to brain receptors inside the BBB. Because of this mechanism, the responses to the two routes of administration are distinctly different. When systemic peptide levels are low, Ang II activates only receptors in the CVOs; however, when these levels are high, the peptide diffuses to receptors that are normally activated only by brain Ang II.
A peptide with high potency and intrinsic activity for stimulating the secretion of corticotropin-like and beta -endorphin-like immunoactivities by cultured anterior pituitary cells has been purified from ovine hypothalamic extracts. The primary structure of this 41-residue corticotropin- and beta -endorphin-releasing factor has been determined to be: H-Ser-Gln-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu- Val-Leu-Glu-Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg- Lys-Leu-Leu-Asp-Ile-Ala-NH2 The synthetic peptide is active in vitro and in vivo.
The daily rhythm of plasma corticosteroid concentration was studied in nonhypophysectomized rats and in hypophysectomized rats implanted with beeswax pellets containing ACTH and T4. In the first experiment, male hypophysectomized rats were placed on a 12-h light, 12-h dark cycle (onset of light, 0600 h) with food and water available ad libitum. Beeswax pellets containing 1.5 mg ACTH and 150 micrograms T4 were implanted sc in these rats. Beginning 4 days after the implantation of ACTH and T4, daily rhythms of plasma corticosteroid concentration were detected in these rats on 3 successive days. The injection of sodium pentobarbital (40 mg/kg BW) or atropine sulfate (10 mg/kg BW) ip at 1200 h blocked the expected rise in plasma corticosteroid concentration at 1800 h in both these rats and a group of intact rats. In the second experiment, adrenal innervation was disrupted by spinal cord transection at the T-7 level. L-1-transected rats served as operated controls, and a third group was maintained as unoperated controls. One week after surgery, daily rhythms of plasma corticosteroid concentration were present in both unoperated and L-1 controls (P less than 0.01) but not in the T-7-transected rats. Inasmuch as an extrapituitary mechanism was capable of maintaining adrenocortical rhythmicity in hypophysectomized rats and disruption of adrenal innervation suppressed adrenocortical rhythmicity, it was hypothesized that adrenal innervation may be an extrapituitary mechanism which has a role in adrenocortical rhythmicity.
The effects of ovine CRF, lysine vasopressin (LVP), and their interrelationships, and rat hypothalamic extract (HME), on ACTH and beta-endorphin release by human pituitary tumor cells from two patients with Nelson's syndrome and one with Cushing's disease and on ACTH and cortisol secretion in vivo were studied. In cultured pituitary tumor cells, both LVP and CRF greatly stimulated ACTH and beta-endorphin release at maximally active concentrations of 0.1 microM and 10 nM, respectively. At these concentrations, the combination of the two substances had an additive or synergistic effect on hormone release. Low concentrations of HME potentiated and/or were synergistic with CRF-mediated ACTH release. In vivo, the combination of CRF (1 microgram/kg) and LVP (10 pressor units) induced greater ACTH release than the sum of the responses to CRF and LVP alone. This synergistic effect of CRF plus LVP concerned only ACTH release, while cortisol release after CRF plus LVP was equivalent to the sum of the maximal increments in this hormone after CRF and LVP alone. The peak levels of cortisol after a combination of CRF and LVP probably reflect the maximum stimulatory capacity of the adrenal cortex. These data support the concept that in man, both ovine CRF and vasopressin are corticotropin-releasing factors which act synergistically. Both substances might well regulate, at the pituitary level, the responsiveness of the pituitary-adrenal axis to stimuli reaching the hypothalamus. A test using ovine CRF and LVP together might provide a better index of total pituitary ACTH reserve than one using the two compounds separately.
The HPA axis is the principal effector of the generalized stress response and crucial for maintaining basal and stress-related homeostasis. There has been an exponential increase in knowledge regarding the interactions among the elements of the HPA axis (CRH, AVP, ACTH, glucocorticoids) and between the HPA axis and the other components of the stress system (locus ceruleus/norepinephrine-sympathetic systems), as well as with the axes responsible for reproduction, growth, and immunity. This new knowledge has allowed association of HPA axis dysfunction, characterized by sustained hyperactivity or hypoactivity, to various pathophysiologic states that cut across the traditional boundaries of medical disciplines. These include a range of psychiatric, endocrine, and inflammatory disorders or susceptibility to such disorders.
Even though functional CRH receptors have been identified in several brain regions by ligand binding, the identity of brain areas expressing the CRH receptor gene has not been described. The recent cloning of the rat CRH receptor gene has permitted us to conduct an in situ hybridization histochemistry study to localize CRH receptor mRNA in brain, using an antisense 35S-labeled riboprobe and autoradiography. In virus- and pathogen-free, unstressed, adult male Sprague-Dawley rats we observed CRH receptor gene expression in several brain regions, most of which had been previously shown to bind radiolabeled CRH. Those regions include the pituitary, olfactory bulb, hippocampal formation, cerebral and cerebellar cortexes, hypothalamus, median eminence, amygdala, olfactory tubercle, choroid plexus, thalamus, and inferior colliculus. Further studies are needed to determine the cell types expressing both CRH receptor mRNA and the CRH receptor peptide in nervous system as well as in peripheral tissues.
Neuropeptides are ubiquitous in the sympathetic system and modulate transmission at the levels of the intermediolateral cell column, sympathetic ganglia, and neuroeffector junctions. Several neuropeptide-containing pathways from the hypothalamus and medulla modulate excitability of preganglionic neurons. Neuropeptides coexist with norepinephrine or acetylcholine in subpopulations of chemically coded, target-specific sympathetic ganglion neurons. Neuropeptide Y is colocalized in adrenergic vasoconstrictor neurons, whereas vasoactive intestinal polypeptide is colocalized in cholinergic sudomotor neurons. Neuropeptide expression is plastic; during development, neurons that switch from a noradrenergic to a cholinergic phenotype increase expression of vasoactive intestinal polypeptide, somatostatin, and substance P. Preganglionic inputs increase neuropeptide Y and inhibit substance P expression. Sympathetic denervation produces sprouting of sensory fibers containing substance P and calcitonin gene-related peptide in target tissues. Neuropeptides from preganglionic fibers (e.g., enkephalin) and primary afferents (e.g., substance P, vasoactive intestinal polypeptide) modulate transmission in sympathetic ganglia. Neuropeptide Y produces vasoconstriction, prejunctional inhibition of norepinephrine release, and postjunctional potentiation of norepinephrine effects. Plasma neuropeptide Y increases during intense sympathoexcitation, hypertension, and pheochromocytoma. Dystrophic neurites containing neuropeptide Y occur in human sympathetic ganglia during aging, diabetes, and dysautonomia. Sympathetic neuropeptides may thus have important clinical implications.
The sympathetic nervous system consists of efferent neurones supplying the viscera. The cell bodies of preganglionic neurones are located in four areas in the thoracolumbar cord; however, the majority are found in the IML. Various tracing techniques have provided information concerning the location of the cell bodies of sympathetic preganglionic neurones projecting into various nerves and ganglia and regulating the adrenal gland, the kidney and the sympathetic supply to skeletal muscle. Numerous supraspinal neurones project to the neuropil surrounding sympathetic preganglionic neurones and may form synaptic contacts with these neurones. The areas of the brain that project to the IML appear to be part of a network of reciprocally connected supraspinal cell groups. Although much emphasis has been placed on the importance of the RVLM in the mediation of tonic and phasic inputs to sympathetic preganglionic neurones, it appears that other areas are of significant import; the RVLM should not be considered to be 'the vasomotor centre'. Spinal and cranial afferents influence the sympathetic nervous system. Baroreceptor afferents terminate in the NTS and may utilize an excitatory amino acid as their neurotransmitter. However, a number of neuropeptides are also associated with these afferents. Neurones within the NTS project to a number of brain stem areas thought to be involved in the regulation of sympathetic activity; consequently the baroreceptor reflex may be mediated over a number of parallel pathways involving both supraspinal and spinal sites of inhibition. Many neurotransmitters are thought to regulate the activity of sympathetic preganglionic neurons: monoamines, peptides and amino acids. Matching the chemical content of the cell bodies of neurones within a particular cell group with physiological characteristics is a challenging task; some barosensitive neurones of the RVLM do not appear to be adrenergic although they are in the midst of the C1 adrenergic cell group. Besides acetylcholine and noradrenaline, neurotransmission in the periphery appears to involve numerous peptides and ATP.
This study has sought to investigate whether diabetic neuropathy is a major determinant of the basal tone of the hypothalamic-pituitary-adrenal axis in diabetes mellitus. We have analyzed the changes in ACTH and cortisol by measuring hourly samples from 0800-1900 h in diabetic patients carefully characterized for the presence of neuropathy. The circadian variation for ACTH and cortisol was normal in these patients. However, integrated secretion (area under the curve) of both ACTH and cortisol was increased specifically in the 25 diabetic patients with symptomatic polyneuropathy (43 +/- 20 pmol/L and 3609 +/- 169 nmol/L, respectively) compared to 19 diabetic patients without neuropathy (30 +/- 10 pmol/L and 2800 +/- 690 nmol/L, respectively) (P < 0.02) and to 11 normal controls (26 +/- 10 pmol/L and 2694 +/- 476 nmol/L, respectively) (P < 0.007). These differences occurred independently of the type of diabetes and were significant for most individual time points. ACTH and cortisol concentrations correlated with most clinical and neurophysiological parameters of neuropathy (P < 0.05-0.001), but not with glycemic control, retinopathy, or proteinuria. Overall, these results suggest that diabetic neuropathy is associated with a specific and persistent increase in the activity of the hypothalamic-pituitary-adrenal axis.
The effect of psychological and psychophysical stress on pentobarbital (PbNa)-induced sleeping time was examined in rats to clarify the influence of psychological stress on arousal. Psychological stress and electric footshock of 5-60 min duration significantly shortened PbNa-induced sleeping time, and the shortening was reversed by intracerebroventricular administration of a corticotropin-releasing hormone (CRH)-receptor antagonist. Electrical footshock and restraint significantly raised plasma adrenocorticotropin (ACTH) and catecholamine levels, whereas psychological stress did not significantly affect the plasma hormones levels. These results suggest that both psychological and psychophysical stress increase arousal through brain CRH. It is also concluded that expression of the central nervous system action of CRH, such as increasing arousal, is not necessarily accompanied by a significant increase in the secretion of ACTH and catecholamine in psychological stress.
Corticotropin-releasing factor (CRF) is a 41-amino acid neuropeptide, which is recognized as a critical mediator of complimentary, stress-related endocrine, autonomic, and behavioral responses in mammalian species. CRF belongs to a family of structurally related peptides including frogskin sauvagine and fish urotensin I. The effects of CRF and related peptides are mediated by two distinct receptors, which differ in their anatomical distribution, as well as in their pharmacological characteristics. In addition, CRF is bound with high affinity by a CRF binding protein (CRF-BP), which is a putative inhibitor of CRF action. CRF is probably not the sole endogenous ligand for CRF receptors or the CRF-BP, since a second mammalian member of the CRF family, urocortin, has recently been identified. This article describes recent findings with respect to CRF, its receptors, binding protein, and CRF-related peptides, which provide further insights into the role and mechanisms of CRF action in stress responses.
Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.