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Sample records for adrenal hpa axis

  1. Mifepristone Accelerates HPA Axis Recovery in Secondary Adrenal Insufficiency.

    PubMed

    Cohan, Pejman

    2016-01-01

    Context. Transient secondary adrenal insufficiency (SAI) is an expected complication following successful adenomectomy of ACTH-secreting pituitary adenomas or unilateral adrenalectomy for cortisol-secreting adrenal adenomas. To date, no pharmacological therapy has been shown to hasten recovery of the hypothalamic-pituitary-adrenal (HPA) axis in this clinical scenario. Case Description. A 33-year-old woman underwent uncomplicated unilateral adrenalectomy for a 3.7 cm cortisol-secreting adrenal adenoma. Postoperatively, she developed SAI and was placed on hydrocortisone 15 mg/day, given in divided doses. In the ensuing six years, the patient's HPA axis failed to recover and she remained corticosteroid-dependent. Quarterly biochemical testing (after withholding hydrocortisone for 18 hours) consistently yielded undetectable serum cortisol and subnormal plasma ACTH levels. While she was on hydrocortisone 15 mg/day, mifepristone was initiated and gradually titrated to a maintenance dose of 600 mg/day after 5 months. Rapid recovery of the HPA axis was subsequently noted with ACTH rising into the supranormal range at 4 months followed by a subsequent rise in cortisol levels into the normal range. After 6 months, the dose of hydrocortisone and mifepristone was lowered and both were ultimately stopped after 8 months. The HPA axis remains normal after an additional 16 months of follow-up. Conclusion. Mifepristone successfully restored the HPA axis in a woman with prolonged secondary adrenal insufficiency (SAI) after adrenalectomy for Cushing's syndrome (CS).

  2. Mifepristone Accelerates HPA Axis Recovery in Secondary Adrenal Insufficiency.

    PubMed

    Cohan, Pejman

    2016-01-01

    Context. Transient secondary adrenal insufficiency (SAI) is an expected complication following successful adenomectomy of ACTH-secreting pituitary adenomas or unilateral adrenalectomy for cortisol-secreting adrenal adenomas. To date, no pharmacological therapy has been shown to hasten recovery of the hypothalamic-pituitary-adrenal (HPA) axis in this clinical scenario. Case Description. A 33-year-old woman underwent uncomplicated unilateral adrenalectomy for a 3.7 cm cortisol-secreting adrenal adenoma. Postoperatively, she developed SAI and was placed on hydrocortisone 15 mg/day, given in divided doses. In the ensuing six years, the patient's HPA axis failed to recover and she remained corticosteroid-dependent. Quarterly biochemical testing (after withholding hydrocortisone for 18 hours) consistently yielded undetectable serum cortisol and subnormal plasma ACTH levels. While she was on hydrocortisone 15 mg/day, mifepristone was initiated and gradually titrated to a maintenance dose of 600 mg/day after 5 months. Rapid recovery of the HPA axis was subsequently noted with ACTH rising into the supranormal range at 4 months followed by a subsequent rise in cortisol levels into the normal range. After 6 months, the dose of hydrocortisone and mifepristone was lowered and both were ultimately stopped after 8 months. The HPA axis remains normal after an additional 16 months of follow-up. Conclusion. Mifepristone successfully restored the HPA axis in a woman with prolonged secondary adrenal insufficiency (SAI) after adrenalectomy for Cushing's syndrome (CS). PMID:27516913

  3. Mifepristone Accelerates HPA Axis Recovery in Secondary Adrenal Insufficiency

    PubMed Central

    2016-01-01

    Context. Transient secondary adrenal insufficiency (SAI) is an expected complication following successful adenomectomy of ACTH-secreting pituitary adenomas or unilateral adrenalectomy for cortisol-secreting adrenal adenomas. To date, no pharmacological therapy has been shown to hasten recovery of the hypothalamic-pituitary-adrenal (HPA) axis in this clinical scenario. Case Description. A 33-year-old woman underwent uncomplicated unilateral adrenalectomy for a 3.7 cm cortisol-secreting adrenal adenoma. Postoperatively, she developed SAI and was placed on hydrocortisone 15 mg/day, given in divided doses. In the ensuing six years, the patient's HPA axis failed to recover and she remained corticosteroid-dependent. Quarterly biochemical testing (after withholding hydrocortisone for 18 hours) consistently yielded undetectable serum cortisol and subnormal plasma ACTH levels. While she was on hydrocortisone 15 mg/day, mifepristone was initiated and gradually titrated to a maintenance dose of 600 mg/day after 5 months. Rapid recovery of the HPA axis was subsequently noted with ACTH rising into the supranormal range at 4 months followed by a subsequent rise in cortisol levels into the normal range. After 6 months, the dose of hydrocortisone and mifepristone was lowered and both were ultimately stopped after 8 months. The HPA axis remains normal after an additional 16 months of follow-up. Conclusion. Mifepristone successfully restored the HPA axis in a woman with prolonged secondary adrenal insufficiency (SAI) after adrenalectomy for Cushing's syndrome (CS). PMID:27516913

  4. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)###

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral functions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  5. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) Axis Following Extended Exposure to Atrazine (ATR)

    EPA Science Inventory

    While it is known that adrenal steroids impact reproduction and a variety of other physiological and behavioral fimctions, disruption of the HPA-axis is not typically considered in toxicological studies. Here we characterize changes in basal corticosterone (CORT) and progesterone...

  6. Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis.

    PubMed

    Marković, Vladimir M; Čupić, Željko; Maćešić, Stevan; Stanojević, Ana; Vukojević, Vladana; Kolar-Anić, Ljiljana

    2016-03-01

    A mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis with cholesterol as a dynamical variable was derived to investigate the effects of cholesterol, the primary precursor of all steroid hormones, on the ultradian and circadian HPA axis activity. To develop the model, the parameter space was systematically examined by stoichiometric network analysis to identify conditions for ultradian oscillations, determine conditions under which dynamic transitions, i.e. bifurcations occur and identify bifurcation types. The bifurcations were further characterized using numerical simulations. Model predictions agree well with empirical findings reported in the literature, indicating that cholesterol levels may critically affect the global dynamics of the HPA axis. The proposed model provides a base for better understanding of experimental observations, it may be used as a tool for designing experiments and offers useful insights into the characteristics of basic dynamic regulatory mechanisms that, when impaired, may lead to the development of some modern-lifestyle-associated diseases.

  7. Skin under the (Spot)-Light: Cross-Talk with the Central Hypothalamic-Pituitary-Adrenal (HPA) Axis.

    PubMed

    Jozic, Ivan; Stojadinovic, Olivera; Kirsner, Robert S F; Tomic-Canic, Marjana

    2015-06-01

    UV radiation is among the most prevalent stressors in humans and diurnal rodents, exerting direct and indirect DNA damage, free-radical production, and interaction with specific chromophores that affects numerous biological processes. In addition to its panoply of effects, UVB (290-320 nm) radiation can specifically affect various local neuroendocrine activities by stimulating the expression of corticotropin-releasing hormone (CRH), urocortin, proopiomelanocortin (POMC), and POMC-derived peptides. Although very little is known about the interplay between the central hypothalamic-pituitary-adrenal (HPA) axis and the skin HPA axis analog, in the current issue Skobowiat and Slominski propose a novel mechanism by which exposure to UVB activates a local HPA axis in skin, which in turn activates the central HPA axis, with the requirement of a functional pituitary gland. This is the first evidence of the local HPA axis in skin contributing to the central neuroendocrine response. This raises intriguing possibilities regarding how local production of cortisol and other HPA axis molecules in skin influence overall systemic levels of cortisol and help regulate local and central HPA axes in the context of homeostasis, skin injury, and inflammatory skin disorders.

  8. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome

    PubMed Central

    Chang, L.; Sundaresh, S.; Elliott, J.; Anton, P. A.; Baldi, P.; Licudine, A.; Mayer, M.; Vuong, T.; Hirano, M.; Naliboff, B. D.; Ameen, V. Z.; Mayer, E. A.

    2009-01-01

    Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain. PMID:18684212

  9. Anxiety, coping skills and hypothalamus-pituitary-adrenal (HPA) axis in patients with endometriosis

    PubMed Central

    Quiñones, Maria; Urrutia, Rebecca; Torres-Reverón, Annelyn; Vincent, Katy; Flores, Idhaliz

    2015-01-01

    Background Endometriosis is an inflammatory disease that is defined by growth of endometrial tissue outside the uterus, resulting in pain, infertility, and emotional distress. Previous studies have shown that the HPA axis is compromised in patients with chronic, painful diseases, including endometriosis. However, the underlying mechanisms and the physiological and emotional consequences of dysfunctions in the HPA axis in these patients are largely unknown. We aimed to understand whether diurnal circulating cortisol levels in women with endometriosis are affected and how this impacts their emotional and behavioral responses. Methods Thirty-two patients with endometriosis and 36 healthy control women provided saliva samples and completed a series of psychological questionnaires. Salivary cortisol levels were measured in duplicate using a colorimetric immunoassay. Results There were significant differences in average cortisol levels between endometriosis patients and controls. A negative correlation was found between cortisol levels and infertility and dyspareunia. Furthermore, incapacitating pain was found to be a strong predictor of hypocortisolism. Women with endometriosis reported higher levels of trait anxiety, but showed no differences in perceived stress or in coping styles compared to the control group. Conclusions This study supports previous reports of hypocortisolism as a biomarker of aberrant HPA responses in women with endometriosis. Moreover, it provides further insight into the link between HPA axis dysregulation, emotional responses, and the high comorbidity between endometriosis and other inflammatory conditions. PMID:26900480

  10. The hypothalamo-pituitary-adrenal (HPA) axis in sheep is attenuated during lactation in response to psychosocial and predator stress.

    PubMed

    Ralph, C R; Tilbrook, A J

    2016-04-01

    Activation of the hypothalamo-pituitary-adrenal (HPA) axis by psychosocial stress is attenuated during lactation. We tested the hypothesis that lactating ewes will have attenuated HPA axis responses to isolation and restraint but will have greater responses to predator stress in the form of barking dogs. We imposed two 4 h stressors: psychosocial stress (isolation and restraint of ewes) and predator stress (barking dogs). Blood was collected intravenous every 10 min from nonlactating ewes (n = 6), lactating ewes with lambs present but not able to be suckled (n = 6), and lactating ewes with lambs present and able to be suckled (n = 6). Plasma cortisol and oxytocin were measured. For nonlactating ewes, cortisol increased (P < 0.01) in response to both stressors, and these increases were greater (P < 0.01) than that in the lactating animals. For lactating ewes with lambs present but unable to be suckled, cortisol increased (P < 0.05) in response to both stressors with a greater response to barking dogs (P < 0.05). For lactating ewes with lambs present and able to be suckled, cortisol increased (P < 0.01) in response to barking dogs only. Plasma oxytocin was greater (P < 0.01) in lactating ewes than in nonlactating ewes and did not change in response to the stressors. In conclusion, lactating ewes are likely to have a greater HPA axis response to a stressor that may be perceived to threaten the welfare of themselves and/or their offspring. The role of oxytocin in attenuation of the HPA axis to stress in sheep is unclear from the current research and requires further investigation.

  11. The hypothalamo-pituitary-adrenal (HPA) axis in sheep is attenuated during lactation in response to psychosocial and predator stress

    PubMed Central

    Ralph, C.R.; Tilbrook, A.J.

    2016-01-01

    Activation of the hypothalamo-pituitary-adrenal (HPA) axis by psychosocial stress is attenuated during lactation. We tested the hypothesis that lactating ewes will have attenuated HPA axis responses to isolation and restraint but will have greater responses to predator stress in the form of barking dogs. We imposed two 4 h stressors: psychosocial stress (isolation and restraint of ewes) and predator stress (barking dogs). Blood was collected intravenous every 10 min from nonlactating ewes (n = 6), lactating ewes with lambs present but not able to be suckled (n = 6), and lactating ewes with lambs present and able to be suckled (n = 6). Plasma cortisol and oxytocin were measured. For nonlactating ewes, cortisol increased (P < 0.01) in response to both stressors, and these increases were greater (P < 0.01) than that in the lactating animals. For lactating ewes with lambs present but unable to be suckled, cortisol increased (P < 0.05) in response to both stressors with a greater response to barking dogs (P < 0.05). For lactating ewes with lambs present and able to be suckled, cortisol increased (P < 0.01) in response to barking dogs only. Plasma oxytocin was greater (P < 0.01) in lactating ewes than in nonlactating ewes and did not change in response to the stressors. In conclusion, lactating ewes are likely to have a greater HPA axis response to a stressor that may be perceived to threaten the welfare of themselves and/or their offspring. The role of oxytocin in attenuation of the HPA axis to stress in sheep is unclear from the current research and requires further investigation. PMID:26773370

  12. Fetal and Neonatal HPA Axis.

    PubMed

    Wood, Charles E; Walker, Claire-Dominique

    2015-01-01

    Stress is an integral part of life. Activation of the hypothalamus-pituitary-adrenal (HPA) axis in the adult can be viewed as mostly adaptive to restore homeostasis in the short term. When stress occurs during development, and specifically during periods of vulnerability in maturing systems, it can significantly reprogram function, leading to pathologies in the adult. Thus, it is critical to understand how the HPA axis is regulated during developmental periods and what are the factors contributing to shape its activity and reactivity to environmental stressors. The HPA axis is not a passive system. It can actively participate in critical physiological regulation, inducing parturition in the sheep for instance or being a center stage actor in the preparation of the fetus to aerobic life (lung maturation). It is also a major player in orchestrating mental function, metabolic, and cardiovascular function often reprogrammed by stressors even prior to conception through epigenetic modifications of gametes. In this review, we review the ontogeny of the HPA axis with an emphasis on two species that have been widely studied-sheep and rodents-because they each share many similar regulatory mechanism applicable to our understanding of the human HPA axis. The studies discussed in this review should ultimately inform us about windows of susceptibility in the developing brain and the crucial importance of early preconception, prenatal, and postnatal interventions designed to improve parental competence and offspring outcome. Only through informed studies will our public health system be able to curb the expansion of many stress-related or stress-induced pathologies and forge a better future for upcoming generations.

  13. Sex differences in the HPA axis.

    PubMed

    Goel, Nirupa; Workman, Joanna L; Lee, Tiffany T; Innala, Leyla; Viau, Victor

    2014-07-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a major component of the systems that respond to stress, by coordinating the neuroendocrine and autonomic responses. Tightly controlled regulation of HPA responses is critical for maintaining mental and physical health, as hyper- and hypo-activity have been linked to disease states. A long history of research has revealed sex differences in numerous components of the HPA stress system and its responses, which may partially form the basis for sex disparities in disease development. Despite this, many studies use male subjects exclusively, while fewer reports involve females or provide direct sex comparisons. The purpose of this article is to present sex comparisons in the functional and molecular aspects of the HPA axis, through various phases of activity, including basal, acute stress, and chronic stress conditions. The HPA axis in females initiates more rapidly and produces a greater output of stress hormones. This review focuses on the interactions between the gonadal hormone system and the HPA axis as the key mediators of these sex differences, whereby androgens increase and estrogens decrease HPA activity in adulthood. In addition to the effects of gonadal hormones on the adult response, morphological impacts of hormone exposure during development are also involved in mediating sex differences. Additional systems impinging on the HPA axis that contribute to sex differences include the monoamine neurotransmitters norepinephrine and serotonin. Diverse signals originating from the brain and periphery are integrated to determine the level of HPA axis activity, and these signals are, in many cases, sex-specific.

  14. Stress and the HPA Axis

    PubMed Central

    Stephens, Mary Ann C.; Wand, Gary

    2012-01-01

    Stress has long been suggested to be an important correlate of uncontrolled drinking and relapse. An important hormonal response system to stress—the hypothalamic–pituitary–adrenal (HPA) axis—may be involved in this process, particularly stress hormones known as glucocorticoids and primarily cortisol. The actions of this hormone system normally are tightly regulated to ensure that the body can respond quickly to stressful events and return to a normal state just as rapidly. The main determinants of HPA axis activity are genetic background, early-life environment, and current life stress. Alterations in HPA axis regulation are associated with problematic alcohol use and dependence; however, the nature of this dysregulation appears to vary with respect to stage of alcohol dependence. Much of this research has focused specifically on the role of cortisol in the risk for, development of, and relapse to chronic alcohol use. These studies found that cortisol can interact with the brain’s reward system, which may contribute to alcohol’s reinforcing effects. Cortisol also can influence a person’s cognitive processes, promoting habit-based learning, which may contribute to habit formation and risk of relapse. Finally, cortisol levels during abstinence may be useful clinical indicators of relapse vulnerability in alcohol-dependent people. PMID:23584113

  15. Investigation of the hypothalamo-pituitary-adrenal axis (HPA) by 1 microg ACTH test and metyrapone test in patients with primary fibromyalgia syndrome.

    PubMed

    Calis, M; Gökçe, C; Ates, F; Ulker, S; Izgi, H B; Demir, H; Kirnap, M; Sofuoglu, S; Durak, A C; Tutus, A; Kelestimur, F

    2004-01-01

    Primary fibromyalgia syndrome (PFS) is characterized by widespread chronic pain that affects the musculoskeletal system, fatigue, anxiety, sleep disturbance, headache and postural hypotension. The pathophysiology of PFS is unknown. The hypothalamic-pituitary-adrenal (HPA) axis seems to play an important role in PFS. Both hyperactivity and hypoactivity of the HPA axis have been reported in patients with PFS. In this study we assessed the HPA axis by 1 microg ACTH stimulation test and metyrapone test in 22 patients with PFS and in 15 age-, sex-, and body mass index (BMI)- matched controls. Metyrapone (30 mg/kg) was administered orally at 23:00 h and blood was sampled at 08:30 h the following morning for 11-deoxycortisol. ACTH stimulation test was carried out by using 1 microg (iv) ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0, 30 and 60 min. Peak cortisol level (659.4 +/- 207.2 nmol/l) was lower in the patients with PFS than peak cortisol level (838.7 +/- 129.6 nmol/l) in the control subjects (p < 0.05). Ten patients (45%) with PFS had peak cortisol responses to 1 microg ACTH test lower than the lowest peak cortisol detected in healthy controls. After metyrapone test 11-deoxycortisol level was 123.7 +/- 26 nmol/l in patients with PFS and 184.2 +/- 17.3 nmol/l in the controls (p < 0.05). Ninety five percent of the patients with PFS had lower 11-deoxycortisol level after metyrapone than the lowest 11-deoxycortisol level after metyrapone detected in healthy controls. We also compared the adrenal size of the patients with that of the healthy subjects and we found that the adrenal size between the groups was similar. This study clearly shows that HPA axis is underactivated in PFS, rather than overactivated. PMID:15053242

  16. Effects of atrazine (ATR), deisopropylatrazine (DIA), Diaminochlorotriazine (DACT) on the hypothalamic-pituitary-adrenal (HPA) axis in female rats

    EPA Science Inventory

    We previously reported that a single dose of the herbicide ATR stimulated the HPA axis in the male rat while equimolar doses of its primary metabolite, DACT, had a minimal effect. In this study, we evaluated the effects of one or four daily doses of ATR, DACT, and an intermediat...

  17. EFFECTS OF ATRAZINE (ATR), DEISOPROPYLATRAZINE (DIA), AND DIAMINOCHLOROTRIAZINE (DACT) ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN FEMALE RATS

    EPA Science Inventory

    Previously we reported that a single dose of ATR herbicide stimulated HPA axis activation in the male rat while its primary metabolite, DACT, did so to a lesser extent. In this study, we evaluated the effects of ATR, DACT, and an intermediate metabolite, DIA, on adrenocorticotrop...

  18. Recovery by N-acetylcysteine from subchronic exposure to Imidacloprid-induced hypothalamic-pituitary-adrenal (HPA) axis tissues injury in male rats.

    PubMed

    Annabi, Alya; Dhouib, Ines Bini; Lamine, Aicha Jrad; El Golli, Nargès; Gharbi, Najoua; El Fazâa, Saloua; Lasram, Mohamed Montassar

    2015-01-01

    Imidacloprid is the most important example of the neonicotinoid insecticides known to target the nicotinic acetylcholine receptor in insects, and potentially in mammals. N-Acetyl-l-cysteine (NAC) has been shown to possess curative effects in experimental and clinical investigations. The present study was designed to evaluate the recovery effect of NAC against Imidacloprid-induced oxidative stress and cholinergic transmission alteration in hypothalamic-pituitary-adrenal (HPA) axis of male rats following subchronic exposure. About 40 mg/kg of Imidacloprid was administered daily by intragastric intubation and 28 days later, the rats were sacrificed and HPA axis tissues were removed for different analyses. Imidacloprid increased adrenal relative weight and cholesterol level indicating an adaptive stage of the general alarm reaction to stress. Moreover, Imidacloprid caused a significant increase in malondialdehyde level, the antioxidants catalase, superoxide dismutase and glutathione-S-transferase showed various alterations following administration and significant depleted thiols content was only recorded in hypothalamic tissue. Furthermore, the hypothalamic and pituitary acetylcholinesterase activity and calcium level were significantly increased highlighting the alteration of cholinergic activity. The present findings revealed that HPA axis is a sensitive target to Imidacloprid (IMI). Interestingly, the use of NAC for only 7 days post-exposure to IMI showed a partial therapeutic effect against Imidacloprid toxicity.

  19. Ewes With Divergent Cortisol Responses to ACTH Exhibit Functional Differences in the Hypothalamo-Pituitary-Adrenal (HPA) Axis.

    PubMed

    Hewagalamulage, Sakda D; Clarke, Iain J; Rao, Alexandra; Henry, Belinda A

    2016-09-01

    Within any population, the cortisol response to ACTH covers a considerable range. High responders (HRs) exhibit a greater cortisol secretory response to stress or ACTH, compared with individuals classified as low cortisol responders (LRs). We administered ACTH (0.2 μg/kg, iv) to 160 female sheep and selected subpopulations of animals as LR and HR. In the present study, we aimed to characterize the hypothalamo-pituitary-adrenal axis in HR and LR and to identify factors that underlie the differing cortisol responses to ACTH. Hypothalami, pituitaries, and adrenals were collected from nonstressed HR and LR ewes. Expression of genes for CRH, arginine vasopressin (AVP), oxytocin, glucocorticoid receptor, and mineralocorticoid receptor were measured by in situ hybridization in the paraventricular nucleus of the hypothalamus, and proopiomelanocortin (POMC) gene expression was measured in the anterior pituitary. Expression of CRH, AVP, and POMC was higher in HR, with no differences in either glucocorticoid receptor or mineralocorticoid receptor expression. Oxytocin expression was greater in LR. In the adrenal gland, real-time PCR analysis indicated that expression of the ACTH receptor and a range of steroidogenic enzymes was similar in HR and LR. Adrenal weights, the cortex to medulla ratio and adrenal cortisol content were also similar in LR and HR. In conclusion, LR and HR display innate differences in the steady-state expression of CRH, AVP, oxytocin, and POMC, indicating that selection for cortisol responsiveness identifies distinct subpopulations that exhibit innate differences in the gene expression/function of hypothalamo-pituitary-adrenal axis markers. PMID:27414744

  20. Corticosterone, brain mineralocorticoid receptors (MRs) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis: the Lewis rat as an example of increased central MR capacity and a hyporesponsive HPA axis.

    PubMed

    Oitzl, M S; van Haarst, A D; Sutanto, W; de Kloet, E R

    1995-01-01

    In this study we report a series of differences in brain and peripheral elements regulating the hypothalamic-pituitary-adrenal (HPA) axis between male LEW and Wistar rats. We found: (i) differential properties of mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the brain (hippocampus, hypothalamus) and pituitary: LEW rats displayed an increased capacity of MRs in the hippocampus and hypothalamus and a decreased capacity of glucocorticoid receptors GRs in the pituitary. The binding affinity (Kd) for MRs and GRs in the hippocampus was comparable. (ii) Lower concentrations of corticotropin releasing hormone (CRH) mRNA were detected in the nucleus paraventricularis of the hypothalamus of LEW rats. (iii) Adrenal weight was similar in LEW and Wistar rats; however, LEW rats had about 30% less adrenocortical cells. Subjecting adrenocortical cells to increasing doses of ACTH1-24 in vitro resulted in about a 60% smaller release of corticosterone in LEW rats. (iv) LEW rats escaped dexamethasone suppression showing increased basal levels of endogenous ACTH, but responded with a comparable release of corticosterone to the IV injection of 5 ng ACTH1-24. (v) LEW rats responded to a variety of stimuli: adrenalectomy under ether anaesthesia, a novel environment, a tail nick and restraint or an immunological challenge, with lower circulating ACTH and corticosterone plasma levels than Wistar rats. (vi) Evening levels of ACTH and corticosterone were lower in LEW than Wistar rats but did not differ in the morning. Blockade of brain MRs in the evening by a central injection of the specific MR antagonist RU28318 in LEW rats resulted in increased circulating levels of ACTH and corticosterone. (vii) Levels of corticosteroid-binding proteins were lower in one-day adrenalectomized LEW rats, indicating higher levels of free corticosterone. (viii) LEW rats had a smaller thymus than Wistar rats. Taken together, the receptor binding data correspond to a decreased

  1. Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function, part I: general overview of HPA axis study design.

    PubMed

    Fan, Ying; Ma, Lian; Pippins, Jennifer; Limb, Susan; Xu, Yun; Sahajwalla, Chandrahas G

    2013-10-01

    Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single-ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (<6 weeks) for adult trials and blinded, placebo controlled, and long term (≥6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained.

  2. Effects of aging on hypothalamic-pituitary-adrenal (HPA) axis activity and reactivity in virgin male and female California mice (Peromyscus californicus).

    PubMed

    Harris, Breanna N; Saltzman, Wendy

    2013-06-01

    Life history theory posits that organisms face a trade-off between current and future reproductive attempts. The physiological mechanisms mediating such trade-offs are still largely unknown, but glucocorticoid hormones are likely candidates as elevated, post-stress glucocorticoid levels have been shown to suppress both reproductive physiology and reproductive behavior. Aged individuals have a decreasing window in which to reproduce, and are thus predicted to invest more heavily in current as opposed to future reproduction. Therefore, if glucocorticoids are important in mediating the trade-off between current and future reproduction, aged animals are expected to show decreased hypothalamic-pituitary-adrenal (HPA) axis responses to stressors and to stimulation by corticotropin-releasing hormone (CRH), and enhanced responses to glucocorticoid negative feedback, as compared to younger animals. We tested this hypothesis in the monogamous, biparental California mouse by comparing baseline and post-stress corticosterone levels, as well as corticosterone responses to dexamethasone (DEX) and CRH injections, between old (∼18-20months) and young (∼4months) virgin adults of both sexes. We also measured gonadal and uterine masses as a proxy for investment in potential current reproductive effort. Adrenal glands were weighed to determine if older animal had decreased adrenal mass. Old male mice had lower plasma corticosterone levels 8h after DEX injection than did young male mice, suggesting that the anterior pituitary of older males is more sensitive to DEX-induced negative feedback. Old female mice had higher body-mass-corrected uterine mass than did young females. No other differences in corticosterone levels or organ masses were found between age groups within either sex. In conclusion, we did not find strong evidence for age-related change in HPA activity or reactivity in virgin adult male or female California mice; however, future studies investigating HPA activity and

  3. Effects of aging on hypothalamic-pituitary-adrenal (HPA) axis activity and reactivity in virgin male and female California mice (Peromyscus californicus)

    PubMed Central

    Harris, Breanna N.; Saltzman, Wendy

    2013-01-01

    Life history theory posits that organisms face a trade-off between current and future reproductive attempts. The physiological mechanisms mediating such trade-offs are still largely unknown, but glucocorticoid hormones are likely candidates as elevated, post-stress glucocorticoid levels have been shown to suppress both reproductive physiology and reproductive behavior. Aged individuals have a decreasing window in which to reproduce, and are thus predicted to invest more heavily in current as opposed to future reproduction. Therefore, if glucocorticoids are important in mediating the trade-off between current and future reproduction, aged animals are expected to show decreased hypothalamic-pituitary-adrenal (HPA) axis responses to stressors and to stimulation by corticotropin-releasing hormone (CRH), and enhanced responses to glucocorticoid negative feedback, as compared to younger animals. We tested this hypothesis in the monogamous, biparental California mouse by comparing baseline and post-stress corticosterone levels, as well as corticosterone responses to dexamethasone (DEX) and CRH injections, between old (~18–20 months) and young (~4 months) virgin adults of both sexes. We also measured gonadal and uterine masses as a proxy for investment in potential current reproductive effort. Adrenal glands were weighed to determine if older animal had decreased adrenal mass. Old male mice had lower plasma corticosterone levels 8 h after DEX injection than did young male mice, suggesting that the anterior pituitary of older males is more sensitive to DEX-induced negative feedback. Old female mice had higher body-mass-corrected uterine mass than did young females. No other differences in corticosterone levels or organ masses were found between age groups within either sex. In conclusion, we did not find strong evidence for age-related change in HPA activity or reactivity in virgin adult male or female California mice; however, future studies investigating HPA activity

  4. Hypothalamic-pituitary-adrenal (HPA) axis function in the California mouse (Peromyscus californicus): Changes in baseline activity, reactivity, and fecal excretion of glucocorticoids across the diurnal cycle

    PubMed Central

    Harris, Breanna N.; Saltzman, Wendy; de Jong, Trynke R.; Milnes, Matthew R.

    2012-01-01

    The California mouse, Peromyscus californicus, is an increasingly popular animal model in behavioral, neural, and endocrine studies, but little is known about its baseline hypothalamicpituitary-adrenal (HPA) axis activity or HPA responses to stressors. We characterized plasma corticosterone (CORT) concentrations in P. californicus under baseline conditions across the diurnal cycle, in response to pharmacological manipulation of the HPA axis, and in response to a variety of stressors at different times of day. In addition, we explored the use of fecal samples to monitor adrenocortical activity non-invasively. California mice have very high baseline levels of circulating CORT that change markedly over 24 hours, but that do not differ between the sexes. This species may be somewhat glucocorticoid-resistant in comparison to other rodents as a relatively high dose of dexamethasone (5 mg/kg, s.c.) was required to suppress plasma CORT for 8 h post-injection. CORT responses to stressors and ACTH injection differed with time of day, as CORT concentrations were elevated more readily during the morning (inactive period) than in the evening (active period) when compared to time-matched control. Data from 3H-CORT injection studies show that the time course for excretion of fecal CORT, or glucocorticoid metabolites, differs with time of injection. Mice injected in the evening excreted the majority of fecal radioactivity 2–4 h post-injection whereas mice injected during the morning did so at 14–16 h post-injection. Unfortunately, the antibody we used does not adequately bind the most prevalent fecal glucocorticoid metabolites and therefore we could not validate its use for fecal assays. PMID:23026495

  5. Combined effects of perfluorooctane sulfonate (PFOS) and maternal restraint stress on hypothalamus adrenal axis (HPA) function in the offspring of mice

    SciTech Connect

    Ribes, Diana; Fuentes, Silvia; Torrente, Margarita; Colomina, M. Teresa; Domingo, Jose L.

    2010-02-15

    Although it is known that prenatal exposure to perfluorooctane sulfonate (PFOS) can cause developmental adverse effects in mammals, the disruptive effects of this compound on hormonal systems are still controversial. Information concerning the effects of PFOS on hypothalamus adrenal (HPA) axis response to stress and corticosterone levels is not currently available. On the other hand, it is well established that stress can enhance the developmental toxicity of some chemicals. In the present study, we assessed the combined effects of maternal restraint stress and PFOS on HPA axis function in the offspring of mice. Twenty plug-positive female mice were divided in two groups. Animals were given by gavage 0 and 6 mg PFOS/kg/day on gestation days 12-18. One half of the animals in each group were also subjected to restraint stress (30 min/session, 3 sessions/day) during the same period. Five plug-positive females were also included as non-manipulated controls. At 3 months of age, activity in an open-field and the stress response were evaluated in male and female mice by exposing them to 30 min of restraint stress. Male and female offspring were subsequently sacrificed and blood samples were collected to measure changes in corticosterone levels at four different moments related to stress exposure conditions: before stress exposure, immediately after 30 min of stress exposure, and recuperation levels at 60 and 90 min after stress exposure. Results indicate corticosterone levels were lower in mice prenatally exposed to restraint. In general terms, PFOS exposure decreased corticosterone levels, although this effect was only significant in females. The recuperation pattern of corticosterone was mainly affected by prenatal stress. Interactive effects between PFOS and maternal stress were sex dependent. The current results suggest that prenatal PFOS exposure induced long-lasting effects in mice.

  6. Effortful Control and Parenting: Associations with HPA Axis Reactivity in Early Childhood

    ERIC Educational Resources Information Center

    Kryski, Katie R.; Dougherty, Lea R.; Dyson, Margaret W.; Olino, Thomas M.; Laptook, Rebecca S.; Klein, Daniel N.; Hayden, Elizabeth P.

    2013-01-01

    While activation of the hypothalamic-pituitary-adrenal (HPA) axis is an adaptive response to stress, excessive HPA axis reactivity may be an important marker of childhood vulnerability to psychopathology. Parenting, including parent affect during parent-child interactions, may play an important role in shaping the developing HPA system; however,…

  7. Adolescent Survivors of Hurricane Katrina: A Pilot Study of Hypothalamic-Pituitary-Adrenal Axis Functioning

    ERIC Educational Resources Information Center

    Pfefferbaum, Betty; Tucker, Phebe; Nitiéma, Pascal

    2015-01-01

    Background: The hypothalamic-pituitary-adrenal (HPA) axis constitutes an important biological component of the stress response commonly studied through the measurement of cortisol. Limited research has examined HPA axis dysregulation in youth exposed to disasters. Objective: This study examined HPA axis activation in adolescent Hurricane Katrina…

  8. Exercise and the Hypothalamo-Pituitary-Adrenal Axis.

    PubMed

    Duclos, Martine; Tabarin, Antoine

    2016-01-01

    Exercise represents a potent physiological stimulus upon the hypothalamo-pituitary adrenal (HPA) axis. Two major factors modulate the HPA axis response to exercise: intensity and duration. Endurance training per se does not induce permanent hypercortisolism as endurance-trained subjects have similar biological markers of HPA axis activity in resting condition as healthy untrained men. However, during a challenge of the HPA axis, endurance-trained subjects demonstrate an adaptation of the HPA axis activity to repeated exercise resulting from decreased tissular sensitivity to glucocorticoids. A great diversity of other mechanisms is involved in this adaptation, acting potentially at all levels in the cascade and leading to the biological effects of cortisol. PMID:27348531

  9. Distress calls of the greater short-nosed fruit bat Cynopterus sphinx activate hypothalamic-pituitary-adrenal (HPA) axis in conspecifics.

    PubMed

    Mariappan, Subramanian; Bogdanowicz, Wieslaw; Marimuthu, Ganapathy; Rajan, Koilmani Emmanuvel

    2013-09-01

    In a stressful situation, greater short-nosed fruit bats (Cynopterus sphinx) emit audible vocalization either to warn or to inform conspecifics. We examined the effect of distress calls on bats emitting the call as well as the bats receiving the distress signal through analysis of the hypothalamic-pituitary-adrenal axis and catacholaminargic systems. We measured the levels of neurotransmitters [serotonin (5-HT), dopamine (DA), norepinephrine (NE)] and stress hormones [(adrenocorticotropic hormone (ACTH) and corticosterone (CORT)]. Our results showed that distress call emission elevated the level of ACTH and CORT, as well as 5-HT, DA and NE in the amygdala, for both the call emitting bat and the responding bat. Subsequently, we observed increased activity of glucocorticoid receptor and its steroid receptor co-activator (SRC-1). An expression of SRC-1 was up-regulated in the distress call emitter only, whereas it was at a similar level in both the call responder and silent bats. These findings suggest that bats emitting distress calls and also bats responding to such calls have similar neurotransmitter expression patterns, and may react similarly in response to stress. PMID:23832467

  10. Androgenic influence on serotonergic activation of the HPA stress axis.

    PubMed

    Goel, Nirupa; Plyler, Kimberly S; Daniels, Derek; Bale, Tracy L

    2011-05-01

    The higher incidence of stress-mediated affective disorders in women may be a function of gonadal hormone influence on complex interactions between serotonin and neural circuits that mediate the hypothalamic-pituitary-adrenal (HPA) stress axis. The paraventricular nucleus of the hypothalamus (PVN) receives serotonergic innervation, and selective serotonin reuptake inhibitors such as citalopram activate the HPA axis independent of stress. We have previously demonstrated that the magnitude of this serotonergic activation was greater in females and was attenuated by testosterone administration; however, the potential central sites of action where androgens reduce these serotonergic effects have not been determined. Therefore, we examined a time course of corticosterone production and used central c-Fos protein levels to assay neuronal activation in stress-related brain regions in female, male, and gonadectomized male mice after an acute citalopram injection (15 mg/kg). In the hippocampus, c-Fos-immunoreactivity was greater in males than in females or gonadectomized males. This same pattern emerged in the lateral septum after vehicle and gonadectomy reversed the effect of citalopram. These regions are important for inhibitory influences on the PVN, and accordingly, hippocampal c-Fos levels were negatively correlated with corticosterone production. No sex differences in c-Fos were detected in the PVN, cingulate cortex, or paraventricular thalamus in response to vehicle or citalopram. These data support brain region-specific regulation of the HPA axis where sex differences may be mediated partly through androgen enhancement of signaling in inhibitory regions.

  11. The different roles of glucocorticoids in the hippocampus and hypothalamus in chronic stress-induced HPA axis hyperactivity.

    PubMed

    Zhu, Li-Juan; Liu, Meng-Ying; Li, Huan; Liu, Xiao; Chen, Chen; Han, Zhou; Wu, Hai-Yin; Jing, Xing; Zhou, Hai-Hui; Suh, Hoonkyo; Zhu, Dong-Ya; Zhou, Qi-Gang

    2014-01-01

    Hypothalamus-pituitary-adrenal (HPA) hyperactivity is observed in many patients suffering from depression and the mechanism underling the dysfunction of HPA axis is not well understood. Chronic stress has a causal relationship with the hyperactivity of HPA axis. Stress induces the over-synthesis of glucocorticoids, which will arrive at all the body containing the brain. It is still complicated whether glucocorticoids account for chronic stress-induced HPA axis hyperactivity and in which part of the brain the glucocorticoids account for chronic stress-induced HPA axis hyperactivity. Here, we demonstrated that glucocorticoids were indispensable and sufficient for chronic stress-induced hyperactivity of HPA axis. Although acute glucocorticoids elevation in the hippocampus and hypothalamus exerted a negative regulation of HPA axis, we found that chronic glucocorticoids elevation in the hippocampus but not in the hypothalamus accounted for chronic stress-induced hyperactivity of HPA axis. Chronic glucocorticoids exposure in the hypothalamus still exerted a negative regulation of HPA axis activity. More importantly, we found mineralocorticoid receptor (MR) - neuronal nitric oxide synthesis enzyme (nNOS) - nitric oxide (NO) pathway mediated the different roles of glucocorticoids in the hippocampus and hypothalamus in regulating HPA axis activity. This study suggests that the glucocorticoids in the hippocampus play an important role in the development of HPA axis hyperactivity and the glucocorticoids in the hypothalamus can't induce hyperactivity of HPA axis, revealing new insights into understanding the mechanism of depression.

  12. Bouncing back - trauma and the HPA-axis in healthy adults

    PubMed Central

    Klaassens, Ellen Renée

    2010-01-01

    Background Dysregulation of the hypothalamic–pituitary–adrenal (HPA)-axis is thought to underlie stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD). Some studies have reported HPA-axis dysregulation in trauma-exposed (TE) adults in the absence of psychiatric morbidity. In this dissertation we set out to unravel part of the mechanism that underlies the complex relations between trauma exposure, stress regulation, and psychopathology. Method Mentally healthy TE subjects were compared with non-trauma-exposed (NE) healthy controls. To distinguish between the potential effects of childhood trauma and adulthood trauma, we included women exposed to childhood trauma as well as men who were exposed to trauma during adulthood. Basal HPA-axis functioning was assessed with salivary cortisol samples. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test. Results The results show that childhood trauma exposure is associated with an attenuated cortisol response after the Dex/CRH challenge test in women. In contrast, trauma exposure during adulthood was not associated with alterations in HPA-axis regulation after the Dex/CRH test. Neither childhood trauma nor adulthood trauma were associated with basal HPA-axis functioning. Conclusion Childhood trauma rather than adulthood trauma may chronically affect HPA-axis functioning. Since the association between adulthood trauma and resilience to psychopathology cannot be explained by HPA-axis functioning alone, other factors must play a role. PMID:22893796

  13. Dynamics of the regulation of the hypothalamo-pituitary-adrenal (HPA) axis determined using a nonsurgical method for collecting pituitary venous blood from horses.

    PubMed

    Alexander, S L; Irvine, C H; Donald, R A

    1996-01-01

    Since 1985, we have applied our nonsurgical technique for collecting pituitary venous (PitVen) blood from ambulatory horses to investigate the regulation of adrenocorticotropic hormone (ACTH) secretion. This method offers particular advantages for studying the hypothalamo-pituitary-adrenal axis since its benign nature enables hypothalamic and pituitary interactions to be monitored without disturbing the animal, and the horse's large blood volume allows 3- to 4-ml samples to be collected as frequently as every 20s for prolonged periods so that the secretion patterns of ACTH and its secretagogues can be precisely defined. When PitVen blood was sampled every 20 or 30s during the circadian maximum, arginine vasopressin (AVP) and ACTH secretion patterns were complex and irregular, with mean interpeak intervals of approximately 5 min. Despite their erratic patterns, AVP and ACTH secretions were closely coupled on cross-correlation analysis. By contrast, PitVen corticotropin-releasing hormone (CRH) concentrations were low, relatively stable, and not consistently related to ACTH secretion. However, when cortisol negative feedback was reduced acutely by metyrapone infusion, CRH and AVP secretion were stimulated. Mathematical modeling suggested that CRH had become the more effective secretagogue and that much of the ACTH response was mediated by increased pituitary responsiveness to CRH. Elevated blood osmolality triggered synchronous AVP and ACTH secretion, without altering PitVen CRH. In this case, the source of PitVen AVP was presumably the magnocellular/neurohypophysial pathway, which is thought to respond primarily to changes in blood osmolality and pressure. Our results suggest that this pathway also participates in ACTH regulation. We have studied the effect of several perturbations and found, as have others, that the secretagogues released vary with the stimulus given. For example, vigorous exercise promptly raised PitVen AVP and ACTH, but not PitVen CRH

  14. HPA axis dysregulation in men with hypersexual disorder.

    PubMed

    Chatzittofis, Andreas; Arver, Stefan; Öberg, Katarina; Hallberg, Jonas; Nordström, Peter; Jokinen, Jussi

    2016-01-01

    Hypersexual disorder integrating pathophysiological aspects such as sexual desire deregulation, sexual addiction, impulsivity and compulsivity was suggested as a diagnosis for the DSM-5. However, little is known about the neurobiology behind this disorder. A dysregulation of the hypothalamic pituitary adrenal (HPA) axis has been shown in psychiatric disorders but has not been investigated in hypersexual disorder. The aim of this study was to investigate the function of the HPA axis in hypersexual disorder. The study includes 67 male patients with hypersexual disorder and 39 healthy male volunteers. Basal morning plasma levels of cortisol and ACTH were assessed and low dose (0.5mg) dexamethasone suppression test was performed with cortisol and ACTH measured post dexamethasone administration. Non-suppression status was defined with DST-cortisol levels ≥ 138 nmol/l. The Sexual Compulsive scale (SCS), Hypersexual disorder current assessment scale (HD:CAS), Montgomery-Åsberg Depression Scale-self rating (MADRS-S) and Childhood trauma questionnaire (CTQ), were used for assessing hypersexual behavior, depression severity and early life adversity. Patients with hypersexual disorder were significantly more often DST non-suppressors and had significantly higher DST-ACTH levels compared to healthy volunteers. The patients reported significantly more childhood trauma and depression symptoms compared to healthy volunteers. CTQ scores showed a significant negative correlation with DST-ACTH whereas SCS and HD:CAS scores showed a negative correlation with baseline cortisol in patients. The diagnosis of hypersexual disorder was significantly associated DST non-suppression and higher plasma DST-ACTH even when adjusted for childhood trauma. The results suggest HPA axis dysregulation in male patients with hypersexual disorder. PMID:26519779

  15. HPA axis dysregulation in men with hypersexual disorder.

    PubMed

    Chatzittofis, Andreas; Arver, Stefan; Öberg, Katarina; Hallberg, Jonas; Nordström, Peter; Jokinen, Jussi

    2016-01-01

    Hypersexual disorder integrating pathophysiological aspects such as sexual desire deregulation, sexual addiction, impulsivity and compulsivity was suggested as a diagnosis for the DSM-5. However, little is known about the neurobiology behind this disorder. A dysregulation of the hypothalamic pituitary adrenal (HPA) axis has been shown in psychiatric disorders but has not been investigated in hypersexual disorder. The aim of this study was to investigate the function of the HPA axis in hypersexual disorder. The study includes 67 male patients with hypersexual disorder and 39 healthy male volunteers. Basal morning plasma levels of cortisol and ACTH were assessed and low dose (0.5mg) dexamethasone suppression test was performed with cortisol and ACTH measured post dexamethasone administration. Non-suppression status was defined with DST-cortisol levels ≥ 138 nmol/l. The Sexual Compulsive scale (SCS), Hypersexual disorder current assessment scale (HD:CAS), Montgomery-Åsberg Depression Scale-self rating (MADRS-S) and Childhood trauma questionnaire (CTQ), were used for assessing hypersexual behavior, depression severity and early life adversity. Patients with hypersexual disorder were significantly more often DST non-suppressors and had significantly higher DST-ACTH levels compared to healthy volunteers. The patients reported significantly more childhood trauma and depression symptoms compared to healthy volunteers. CTQ scores showed a significant negative correlation with DST-ACTH whereas SCS and HD:CAS scores showed a negative correlation with baseline cortisol in patients. The diagnosis of hypersexual disorder was significantly associated DST non-suppression and higher plasma DST-ACTH even when adjusted for childhood trauma. The results suggest HPA axis dysregulation in male patients with hypersexual disorder.

  16. In Search of HPA Axis Dysregulation in Child and Adolescent Depression

    ERIC Educational Resources Information Center

    Guerry, John D.; Hastings, Paul D.

    2011-01-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative…

  17. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

    PubMed

    Zaba, Monika; Kirmeier, Thomas; Ionescu, Irina A; Wollweber, Bastian; Buell, Dominik R; Gall-Kleebach, Dominique J; Schubert, Christine F; Novak, Bozidar; Huber, Christine; Köhler, Katharina; Holsboer, Florian; Pütz, Benno; Müller-Myhsok, Bertram; Höhne, Nina; Uhr, Manfred; Ising, Marcus; Herrmann, Leonie; Schmidt, Ulrike

    2015-05-01

    Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity.

  18. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients.

    PubMed

    Zaba, Monika; Kirmeier, Thomas; Ionescu, Irina A; Wollweber, Bastian; Buell, Dominik R; Gall-Kleebach, Dominique J; Schubert, Christine F; Novak, Bozidar; Huber, Christine; Köhler, Katharina; Holsboer, Florian; Pütz, Benno; Müller-Myhsok, Bertram; Höhne, Nina; Uhr, Manfred; Ising, Marcus; Herrmann, Leonie; Schmidt, Ulrike

    2015-05-01

    Analysis of the function of the hypothalamic-pituitary-adrenal (HPA)-axis in patients suffering from posttraumatic stress disorder (PTSD) has hitherto produced inconsistent findings, inter alia in the Trier Social Stress Test (TSST). To address these inconsistencies, we compared a sample of 23 female PTSD patients with either early life trauma (ELT) or adult trauma (AT) or combined ELT and AT to 18 age-matched non-traumatized female healthy controls in the TSST which was preceded by intensive baseline assessments. During the TSST, we determined a variety of clinical, psychological, endocrine and cardiovascular parameters as well as expression levels of four HPA-axis related genes. Using a previously reported definition of HPA-axis responsive versus non-responsive phenotypes, we identified for the first time two clinically and biologically distinct HPA-axis reactivity subgroups of PTSD. One subgroup ("non-responders") showed a blunted HPA-axis response and distinct clinical and biological characteristics such as a higher prevalence of trauma-related dissociative symptoms and of combined AT and ELT as well as alterations in the expression kinetics of the genes encoding for the mineralocorticoid receptor (MR) and for FK506 binding protein 51 (FKBP51). Interestingly, this non-responder subgroup largely drove the relatively diminished HPA axis response of the total cohort of PTSD patients. These findings are limited by the facts that the majority of patients was medicated, by the lack of traumatized controls and by the relatively small sample size. The here for the first time identified and characterized HPA-axis reactivity endophenotypes offer an explanation for the inconsistent reports on HPA-axis function in PTSD and, moreover, suggest that most likely other factors than HPA-axis reactivity play a decisive role in determination of PTSD core symptom severity. PMID:25745955

  19. Age of Trauma Onset and HPA Axis Dysregulation Among Trauma-Exposed Youth.

    PubMed

    Kuhlman, Kate Ryan; Vargas, Ivan; Geiss, Elisa G; Lopez-Duran, Nestor L

    2015-12-01

    The hypothalamic-pituitary-adrenal axis (HPA axis) is a pathway through which childhood trauma may increase risk for negative health outcomes. The HPA axis is sensitive to stress throughout development; however, few studies have examined whether timing of exposure to childhood trauma is related to differences in later HPA axis functioning. Therefore, we examined the association between age of first trauma and HPA axis functioning among adolescents, and whether these associations varied by sex. Parents of 97 youth (aged 9-16 years) completed the Early Trauma Inventory (ETI), and youth completed the Socially-Evaluated Cold-Pressor Task (SECPT). We measured salivary cortisol response to the SECPT, the cortisol awakening response, and diurnal regulation at home across 2 consecutive weekdays. Exposure to trauma during infancy related to delayed cortisol recovery from peak responses to acute stress, d = 0.23 to 0.42. Timing of trauma exposure related to diverging patterns of diurnal cortisol regulation for males, d = 0.55, and females, d = 0.57. Therefore, the HPA axis may be susceptible to developing acute stress dysregulation when exposed to trauma during infancy, whereas the consequences within circadian cortisol regulation may occur in the context of later trauma exposure and vary by sex. Further investigations are warranted to characterize HPA axis sensitivity to exposure to childhood trauma across child development.

  20. Cognitive deficits in relation to personality type and hypothalamic-pituitary-adrenal (HPA) axis dysfunction in women with stress-related exhaustion.

    PubMed

    Sandström, Agneta; Peterson, Jonas; Sandström, Erik; Lundberg, Mattias; Nystrom, Inga-Lill Rhodin; Nyberg, Lars; Olsson, Tommy

    2011-02-01

    Exhaustion caused by long-term work-related stress may cause cognitive dysfunction. We explored factors that may link chronic stress and cognitive impairment. Personality, psychiatric screening, and behavior were assessed by self-reporting measures in 20 female patients (mean age 39.3 years; range 26-53) with a preliminary diagnosis of stress-related exhaustion and in 16 healthy matched controls. Cognitive performance was investigated with a detailed neuropsychological test battery. Cortisol axis function was assessed by urinary and saliva collections of cortisol, dexamethasone suppression, Synacthen response, and corticotropin-releasing hormone (CRH) tests. Proinflammatory cytokines were measured. Hippocampal volumes were estimated by magnetic resonance imaging. Multivariate and univariate statistical methods were used to explore putative differences between groups and factors linked to cognitive impairment. Cognitive function clearly differed between groups, with decreased attention and visuospatial memory in the patient group, suggesting frontal cortex/medial temporal cortex-network dysfunction. Increased harm avoidance and persistence was present among patients, with lowered self-directedness linked to lower quality of life, increased anxious and depressive tendencies, and experiences of psychosocial stress. Attention was decreased with concomitantly impaired visuospatial memory. The pituitary (adrenocorticotropic hormone, ACTH) response to CRH was decreased in patients, with an increased cortisol/ACTH response to CRH. However, cortisol production rates, diurnal or dexamethasone-suppressed saliva cortisol levels, and the cortisol response to Synacthen were unaltered. Hippocampal volumes did not differ between groups. These findings suggest that cognitive dysfunction in stress-related exhaustion is linked to distinct personality traits, low quality of life, and a decreased ACTH response to CRH. PMID:20964695

  1. Seizure-induced disinhibition of the HPA axis increases seizure susceptibility.

    PubMed

    O'Toole, Kate K; Hooper, Andrew; Wakefield, Seth; Maguire, Jamie

    2014-01-01

    Stress is the most commonly reported precipitating factor for seizures. The proconvulsant actions of stress hormones are thought to mediate the effects of stress on seizure susceptibility. Interestingly, epileptic patients have increased basal levels of stress hormones, including corticotropin-releasing hormone (CRH) and corticosterone, which are further increased following seizures. Given the proconvulsant actions of stress hormones, we proposed that seizure-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to future seizure susceptibility. Consistent with this hypothesis, our data demonstrate that pharmacological induction of seizures in mice with kainic acid or pilocarpine increases circulating levels of the stress hormone, corticosterone, and exogenous corticosterone administration is sufficient to increase seizure susceptibility. However, the mechanism(s) whereby seizures activate the HPA axis remain unknown. Here we demonstrate that seizure-induced activation of the HPA axis involves compromised GABAergic control of CRH neurons, which govern HPA axis function. Following seizure activity, there is a collapse of the chloride gradient due to changes in NKCC1 and KCC2 expression, resulting in reduced amplitude of sIPSPs and even depolarizing effects of GABA on CRH neurons. Seizure-induced activation of the HPA axis results in future seizure susceptibility which can be blocked by treatment with an NKCC1 inhibitor, bumetanide, or blocking the CRH signaling with Antalarmin. These data suggest that compromised GABAergic control of CRH neurons following an initial seizure event may cause hyperexcitability of the HPA axis and increase future seizure susceptibility.

  2. Genetic Approaches to Hypothalamic-Pituitary-Adrenal Axis Regulation.

    PubMed

    Arnett, Melinda G; Muglia, Lisa M; Laryea, Gloria; Muglia, Louis J

    2016-01-01

    The normal function of the hypothalamic-pituitary-adrenal (HPA) axis, and resultant glucocorticoid (GC) secretion, is essential for human health. Disruption of GC regulation is associated with pathologic, psychological, and physiological disease states such as depression, post-traumatic stress disorder, hypertension, diabetes, and osteopenia, among others. As such, understanding the mechanisms by which HPA output is tightly regulated in its responses to environmental stressors and circadian cues has been an active area of investigation for decades. Over the last 20 years, however, advances in gene targeting and genome modification in rodent models have allowed the detailed dissection of roles for key molecular mediators and brain regions responsible for this control in vivo to emerge. Here, we summarize work done to elucidate the function of critical neuropeptide systems, GC-signaling targets, and inflammation-associated pathways in HPA axis regulation and behavior, and highlight areas for future investigation.

  3. Differential associations between childhood trauma subtypes and adolescent HPA-axis functioning

    PubMed Central

    Kuhlman, Kate R.; Geiss, Elisa G.; Vargas, Ivan; Lopez-Duran, Nestor L.

    2015-01-01

    Summary Studies examining the association between childhood trauma exposure and neuroendocrine functioning have returned inconsistent findings. To date, few studies have accounted for the role exposure to different types of childhood trauma may have on different neuroendocrine adaptations, and no study has examined this association using multiple indices of hypothalamic—pituitary—adrenal axis (HPA-axis) functioning. The purpose of this study was to characterize the unique associations between exposure to physical abuse, emotional abuse, and non-intentional trauma, and multiple indices of HPA-axis functioning. Methods A community sample of 138 youth (aged 9—16) completed the Socially Evaluated Cold Pressor Task (SE-CPT) while their parents completed the Early Trauma Inventory (ETI). All youth then collected 4 diurnal salivary cortisol samples at home across 2 consecutive weekdays. Results High reported exposure to non-intentional trauma was associated with intact diurnal regulation but elevated cortisol at bedtime, physical abuse was associated with faster reactivity to acute stress, and emotional abuse was associated with delayed recovery of cortisol following acute stress. Taken together, there was a heterogeneous relationship among different indices of HPA-axis functioning and trauma subtype. Discussion Different types of childhood trauma exposure are related to distinct anomalies in HPA-axis functioning. This study underscores the importance of research incorporating multiple indices of HPA-axis functioning to inform our understanding of the underlying neuroendocrine dysregulation that may later lead to stress-related psychopathology. PMID:25704913

  4. Suppression of the HPA axis stress-response: implications for relapse.

    PubMed

    Adinoff, Byron; Junghanns, Klaus; Kiefer, Falk; Krishnan-Sarin, Suchitra

    2005-07-01

    This article presents the proceedings of a symposium held at the meeting of the International Society for Biomedical Research on Alcoholism (ISBRA) in Mannheim, Germany, in October 2004. This symposium explored the potential role of hypothalamic-pituitary-adrenal (HPA) axis dysregulation upon relapse. HPA axis stimulation induces the release of the glucocorticoid cortisol, a compound with profound effects upon behavior and emotion. Altered stress-responses of the HPA axis in abstinent alcohol-dependent subjects, therefore, may influence their affective and behavioral regulation, thus impacting their potential for relapse. Bryon Adinoff began the symposium with a review of HPA axis dysfunction in alcohol-dependent subjects, including recent studies from his lab demonstrating an attenuated glucocorticoid response to both endogenous and exogenous stimulation in one-month abstinent men. Klaus Junghanns presented his work demonstrating that a blunted ACTH or cortisol response to subjective stressors (social stressor or alcohol exposure) is predictive of a return to early drinking. The final two presenters examined the interaction between naltrexone and HPA responsiveness in alcohol-dependent or at-risk subjects, as naltrexone induces an increase in ACTH and cortisol. Falk Kiefer discussed the relationship between basal HPA axis responsivity and clinical outcome following treatment with naltrexone or acamprosate. Plasma ACTH significantly decreased over the course of the study in the placebo group, but not the medication groups [corrected] Lower basal concentrations of ACTH and cortisol were associated with quicker relapse in the placebo group only. Suchitra Krishnan-Sarin described her preliminary work, in which family-history positive (FH+) and family history negative (FH-) subjects were administered naltrexone, followed by an assessment of alcohol-induced craving. The cortisol response to alcohol was significantly and inversely related to craving in the FH+, but not

  5. Metabotropic glutamate receptor-mediated signaling dampens the HPA axis response to restraint stress.

    PubMed

    Evanson, Nathan K; Herman, James P

    2015-10-15

    Glutamate is an important neurotransmitter in the regulation of the neural portion of hypothalamus-pituitary-adrenal (HPA) axis activity, and signals through ionotropic and metabotropic receptors. In the current studies we investigated the role of hypothalamic paraventricular group I metabotropic glutamate receptors in the regulation of the HPA axis response to restraint stress in rats. Direct injection of the group I metabotropic glutamate receptor agonist 3,5-dihydroxyphenylglycine (DHPG) into the PVN prior to restraint leads to blunting of the HPA axis response in awake animals. Consistent with this result, infusion of the group I receptor antagonist hexyl-homoibotenic acid (HIBO) potentiates the HPA axis response to restraint. The excitatory effect of blocking paraventricular group I metabotropic glutamate signaling is blocked by co-administration of dexamethasone into the PVN. However, the inhibitory effect of DHPG is not affected by co-administration of the cannabinoid CB1 receptor antagonist AM-251 into the PVN. Together, these results suggest that paraventricular group I metabotropic glutamate receptor signaling acts to dampen HPA axis reactivity. This effect appears to be similar to the rapid inhibitory effect of glucocorticoids at the PVN, but is not mediated by endocannabinoid signaling.

  6. Neural correlates of parent–child HPA axis coregulation

    PubMed Central

    Saxbe, Darby; Piero, Larissa Del; Margolin, Gayla

    2015-01-01

    Parents and children have been found to show coordination or coregulation of the hypothalamic–pituitary–adrenal (HPA) axis. This coordination may be reflected in adolescents' neural activation to parent stimuli, particularly in regions of the brain associated with social information processing. This study reports on 22 adolescents (13 males, mean age 17 years), recruited from a longitudinal study to participate in a functional MRI (fMRI) scanning protocol. Approximately 1.5 years before the scan, these same adolescents participated in a family conflict discussion in the lab with both parents, and all three family members provided samples of salivary cortisol five times, before and after the discussion. Multilevel models found positive cross-sectional and time-lagged associations between parents' and youth cortisol. Empirical Bayes (EB) coefficients, extracted from these models to reflect the strength of the relationship between parent and adolescent cortisol, were tested in conjunction with adolescents' neural activation to video clips of their parents taken from the conflict discussion. For both mothers and fathers, youth who showed stronger cortisol coregulation with each parent (both in cross-sectional and time-lagged analyses) showed more activation to that same parent in posteromedial regions (precuneus, posterior cingulate, and retrosplenial cortex) that have been linked with social cognition, e.g. mentalizing about others' emotions. Youths' adrenocortical coregulation with their parents may be reflected in their neural processing of stimuli featuring those same parents. PMID:26188122

  7. Neural correlates of parent-child HPA axis coregulation.

    PubMed

    Saxbe, Darby; Del Piero, Larissa; Margolin, Gayla

    2015-09-01

    Parents and children have been found to show coordination or coregulation of the hypothalamic-pituitary-adrenal (HPA) axis. This coordination may be reflected in adolescents' neural activation to parent stimuli, particularly in regions of the brain associated with social information processing. This study reports on 22 adolescents (13 males, mean age 17years), recruited from a longitudinal study to participate in a functional MRI (fMRI) scanning protocol. Approximately 1.5years before the scan, these same adolescents participated in a family conflict discussion in the lab with both parents, and all three family members provided samples of salivary cortisol five times, before and after the discussion. Multilevel models found positive cross-sectional and time-lagged associations between parents' and youth cortisol. Empirical Bayes (EB) coefficients, extracted from these models to reflect the strength of the relationship between parent and adolescent cortisol, were tested in conjunction with adolescents' neural activation to video clips of their parents taken from the conflict discussion. For both mothers and fathers, youth who showed stronger cortisol coregulation with each parent (both in cross-sectional and time-lagged analyses) showed more activation to that same parent in posteromedial regions (precuneus, posterior cingulate, and retrosplenial cortex) that have been linked with social cognition, e.g. mentalizing about others' emotions. Youths' adrenocortical coregulation with their parents may be reflected in their neural processing of stimuli featuring those same parents. PMID:26188122

  8. Overnight suppression of HPA axis after mineraolocorticoid receptor stimulation: A sleep endocrine study.

    PubMed

    Demiralay, Cüneyt; Agorastos, Agorastos; Jahn, Holger; Kellner, Michael; Yassouridis, Alexander; Wiedemann, Klaus

    2015-05-30

    Nocturnal hyperactivity of hypothalamic-pituitary-adrenal axis (HPA) indicates decreased feedback inhibition with stress-related conditions such as major depression and sleep disorders. To characterize the role of mineralocorticoid (MR) in regulation of HPA axis activity during nocturnal sleep and involvement in sleep architecture, we investigated sleep endocrine effects of the MR agonist fludrocortisone in healthy men after pretreatment with metyrapone to minimize the impact of endogenous cortisol. Subjects (n=8) were treated on three occasions in a single-blinded design in random order with a) metyrapone, b) fludrocortisone after metyrapone, and c) placebo. Polysomnography was recorded and blood samples were drawn for determination of adrenocorticotropic hormone (ACTH) and cortisol during the entire night. After metyrapone administration ACTH was significantly enhanced, while overall nocturnal cortisol secretion remained largely unchanged. Whereas administration of fludrocortisone induced a significant inhibitory effect on basal ACTH and cortisol secretion, no considerable effects on sleep pattern were detectable. While the involvement of MR in sleep regulation needs further study, endocrine findings underline the role of MR in tonic regulation of HPA axis during nocturnal sleep and demonstrate the ability of fludrocortisone to further suppress HPA axis activity overnight. Additional studies would be required to evaluate endocrine and clinical fludrocortisone effects in depressive patients showing HPA hyperactivity.

  9. Dynamics of the HPA axis and inflammatory cytokines: Insights from mathematical modeling.

    PubMed

    Malek, Hamed; Ebadzadeh, Mohammad Mehdi; Safabakhsh, Reza; Razavi, Alireza; Zaringhalam, Jalal

    2015-12-01

    In the work presented here, a novel mathematical model was developed to explore the bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory cytokines in acute inflammation. The dynamic model consists of five delay differential equations 5D for two main pro-inflammatory cytokines (TNF-α and IL-6) and two hormones of the HPA axis (ACTH and cortisol) and LPS endotoxin. The model is an attempt to increase the understanding of the role of primary hormones and cytokines in this complex relationship by demonstrating the influence of different organs and hormones in the regulation of the inflammatory response. The model captures the main qualitative features of cytokine and hormone dynamics when a toxic challenge is introduced. Moreover, in this work a new simple delayed model of the HPA axis is introduced which supports the understanding of the ultradian rhythm of HPA hormones both in normal and infection conditions. Through simulations using the model, the role of key inflammatory cytokines and cortisol in transition from acute to persistent inflammation through stability analysis is investigated. Also, by employing a Markov chain Monte Carlo (MCMC) method, parameter uncertainty and the effects of parameter variations on each other are analyzed. This model confirms the important role of the HPA axis in acute and prolonged inflammation and can be a useful tool in further investigation of the role of stress on the immune response to infectious diseases.

  10. Dynamics of the HPA axis and inflammatory cytokines: Insights from mathematical modeling.

    PubMed

    Malek, Hamed; Ebadzadeh, Mohammad Mehdi; Safabakhsh, Reza; Razavi, Alireza; Zaringhalam, Jalal

    2015-12-01

    In the work presented here, a novel mathematical model was developed to explore the bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory cytokines in acute inflammation. The dynamic model consists of five delay differential equations 5D for two main pro-inflammatory cytokines (TNF-α and IL-6) and two hormones of the HPA axis (ACTH and cortisol) and LPS endotoxin. The model is an attempt to increase the understanding of the role of primary hormones and cytokines in this complex relationship by demonstrating the influence of different organs and hormones in the regulation of the inflammatory response. The model captures the main qualitative features of cytokine and hormone dynamics when a toxic challenge is introduced. Moreover, in this work a new simple delayed model of the HPA axis is introduced which supports the understanding of the ultradian rhythm of HPA hormones both in normal and infection conditions. Through simulations using the model, the role of key inflammatory cytokines and cortisol in transition from acute to persistent inflammation through stability analysis is investigated. Also, by employing a Markov chain Monte Carlo (MCMC) method, parameter uncertainty and the effects of parameter variations on each other are analyzed. This model confirms the important role of the HPA axis in acute and prolonged inflammation and can be a useful tool in further investigation of the role of stress on the immune response to infectious diseases. PMID:26476562

  11. Hypothalamic pituitary adrenal axis and prolactin abnormalities in suicidal behavior.

    PubMed

    Pompili, Maurizio; Serafini, Gianluca; Palermo, Mario; Seretti, Maria Elena; Stefani, Henry; Angeletti, Gloria; Lester, David; Amore, Mario; Girardi, Paolo

    2013-11-01

    Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity measured with the dexamethasone suppression test and the dexamethesone/CRH test may have some predictive power for suicidal behavior in patients with mood disorders. Increased prolactin (PRL) levels may be related both to physiological and pathological conditions. HPA-axis abnormalities and increased levels of PRL may coexist, and common neuroendocrine changes may activate both HPA axis and PRL release. HPA-axis hyperactivity is presumably present in a large subpopulation of depressed subjects. Suicidal behavior is considered to be a form of inward-directed aggression, and aggressive behavior has been connected to high androgen levels. However, lower plasma total testosterone levels have also been reported in subjects with depression and higher suicidality. Lipid/immune dysregulations, the increased ratio of blood fatty acids, and increased PRL levels may each be associated with the increased production of pro-inflammatory cytokines, which have been reported in patients with major depression and patients engaging in suicidal behavior. Although no studies have been done to determine whether ante-mortem physical stress may be detected by raised post-mortem PRL, this would be of great interest for physicians.

  12. Charcterization of the Hypothalamic-Pituitary-Adrenal Axis Response to Atrazine and Metabolites in the Female Rat

    EPA Science Inventory

    Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diamino-s-chlorotriazine (DACT), on the HPA axis in...

  13. Alcohol and pregnancy: Effects on maternal care, HPA axis function, and hippocampal neurogenesis in adult females.

    PubMed

    Workman, Joanna L; Raineki, Charlis; Weinberg, Joanne; Galea, Liisa A M

    2015-07-01

    Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous rats. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1-21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis. PMID:25900594

  14. Alcohol and pregnancy: Effects on maternal care, HPA axis function, and hippocampal neurogenesis in adult females.

    PubMed

    Workman, Joanna L; Raineki, Charlis; Weinberg, Joanne; Galea, Liisa A M

    2015-07-01

    Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous rats. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1-21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis.

  15. Hypothalamic Pituitary Adrenal Axis Functioning in Reactive and Proactive Aggression in Children

    ERIC Educational Resources Information Center

    Lopez-Duran, Nestor L.; Olson, Sheryl L.; Hajal, Nastassia J.; Felt, Barbara T.; Vazquez, Delia M.

    2009-01-01

    The purpose of this study was to examine the association between hypothalamic-pituitary-adrenal axis (HPA-axis) reactivity and proactive and reactive aggression in pre-pubertal children. After a 30-min controlled base line period, 73 7-year-old children (40 males and 33 females) were randomly assigned to one of two experimental tasks designed to…

  16. Does HPA-Axis Dysregulation Account for the Effects of Income on Effortful Control and Adjustment in Preschool Children?

    ERIC Educational Resources Information Center

    Lengua, Liliana J.; Zalewski, Maureen; Fisher, Phil; Moran, Lyndsey

    2013-01-01

    The effects of low income on children's adjustment might be accounted for by disruptions to hypothalamic-pituitary-adrenal (HPA)-axis activity and to the development of effortful control. Using longitudinal data and a community sample of preschool-age children (N?=?306, 36-39?months) and their mothers, recruited to over-represent low-income…

  17. Activation of the hypothalamic-pituitary-adrenal stress axis induces cellular oxidative stress

    PubMed Central

    Spiers, Jereme G.; Chen, Hsiao-Jou Cortina; Sernia, Conrad; Lavidis, Nickolas A.

    2015-01-01

    Glucocorticoids released from the adrenal gland in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis induce activity in the cellular reduction-oxidation (redox) system. The redox system is a ubiquitous chemical mechanism allowing the transfer of electrons between donor/acceptors and target molecules during oxidative phosphorylation while simultaneously maintaining the overall cellular environment in a reduced state. The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucocorticoid exposure. PMID:25646076

  18. Effect of reproductive status on hypothalamic-pituitary-adrenal (HPA) activity and reactivity in male California mice (Peromyscus californicus).

    PubMed

    Harris, Breanna N; Saltzman, Wendy

    2013-03-15

    Previous studies indicate that reproductive condition can alter stress response and glucocorticoid release. Although the functional significance of hypothalamic-pituitary-adrenal (HPA) axis modulation by breeding condition is not fully understood, one possible explanation is the behavior hypothesis, which states that an animal's need to express parental behavior may be driving modulation of the HPA axis. This possibility is consistent with findings of blunted activity and reactivity of the HPA axis in lactating female mammals; however, effects of reproductive status on HPA function have not been well characterized in male mammals that express parental behavior. Therefore, we tested this hypothesis in the monogamous and biparental California mouse. Several aspects of HPA activity were compared in males from three reproductive conditions: virgin males (housed with another male), non-breeding males (housed with a tubally ligated female), and first-time fathers (housed with a female and their first litter of pups). In light of the behavior hypothesis we predicted that new fathers would differ from virgin and non-breeding males in several aspects of HPA function and corticosterone (CORT) output: decreased amplitude of the diurnal rhythm in CORT, a blunted CORT increase following predator-odor stress, increased sensitivity to glucocorticoid negative feedback, and/or a blunted CORT response to pharmacological stimulation. In addition, we predicted that first-time fathers would be more resistant to CORT-induced suppression of testosterone secretion, as testosterone is important for paternal behavior in this species. We found that virgin males, non-breeding males and first-time fathers did not display any CORT differences in diurnal rhythm, response to a predator-odor stressor, or response to pharmacological suppression or stimulation. Additionally, there were no differences in circulating testosterone concentrations. Adrenal mass was, however, significantly lower in new

  19. Early-life stress and HPA axis trigger recurrent adulthood depression.

    PubMed

    Juruena, Mario F

    2014-09-01

    It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. During acute stress, adaptive physiological responses occur, which include hyperactivity of the HPA axis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or 'allostasis'. It is correct to state that at the same time that our experiences change our brain and thoughts, namely, changing our mind, we are changing our neurobiology. Increased adrenocortical secretion of hormones, primarily cortisol in major depression, is one of the most consistent findings in neuropsychiatry. A significant percentage of patients with major depression have been shown to exhibit increased concentrations of cortisol, an exaggerated cortisol response to adrenocorticotropic hormone, and an enlargement of both the pituitary and adrenal glands. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of hypothalamic-pituitary-adrenal (HPA) hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood. These abnormalities appear to be related to changes in the ability of hormones to bind to GR and MR receptors. First episodes may begin with an environmental stressor, but if the cycles continue or occur unchecked, the brain

  20. Daily family stress and HPA axis functioning during adolescence: The moderating role of sleep.

    PubMed

    Chiang, Jessica J; Tsai, Kim M; Park, Heejung; Bower, Julienne E; Almeida, David M; Dahl, Ronald E; Irwin, Michael R; Seeman, Teresa E; Fuligni, Andrew J

    2016-09-01

    The present study examined the moderating role of sleep in the association between family demands and conflict and hypothalamic-pituitary-adrenal (HPA) axis functioning in a sample of ethnically diverse adolescents (n=316). Adolescents completed daily diary reports of family demands and conflict for 15 days, and wore actigraph watches during the first 8 nights to assess sleep. Participants also provided five saliva samples for 3 consecutive days to assess diurnal cortisol rhythms. Regression analyses indicated that sleep latency and efficiency moderated the link between family demands and the cortisol awakening response. Specifically, family demands were related to a smaller cortisol awakening response only among adolescents with longer sleep latency and lower sleep efficiency. These results suggest that certain aspects of HPA axis functioning may be sensitive to family demands primarily in the context of longer sleep latency and lower sleep efficiency.

  1. What are the Links Between Maternal Social Status, Hippocampal Function, and HPA Axis Function in Children?

    PubMed Central

    Sheridan, Margaret A.; How, Joan; Araujo, Melanie; Schamberg, Michelle A.; Nelson, Charles A.

    2013-01-01

    The association of parental social status with multiple health and achievement indicators in adulthood has driven researchers to attempt to identify mechanisms by which social experience in childhood could shift developmental trajectories. Some accounts for observed linkages between parental social status in childhood and health have hypothesized that early stress exposure could result in chronic disruptions in hypothalamic-pituitary-adrenal (HPA) axis activation, and that this activation could lead to long term changes. A robust literature in adult animals has demonstrated that chronic HPA axis activation leads to changes in hippocampal structure and function. In the current study, consistent with studies in animals, we observe an association between both maternal self-rated social status and hippocampal activation in children and between maternal self-rated social status and salivary cortisol in children. PMID:24033572

  2. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

    PubMed

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Divan, Ali; Grant, Stephanie; Patel, Nisha; Newell-Rogers, Karen; DeMorrow, Sharon

    2015-12-01

    Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease.

  3. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

    PubMed

    Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung

    2016-09-01

    Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder.

  4. Post-stress rumination predicts HPA axis responses to repeated acute stress.

    PubMed

    Gianferante, Danielle; Thoma, Myriam V; Hanlin, Luke; Chen, Xuejie; Breines, Juliana G; Zoccola, Peggy M; Rohleder, Nicolas

    2014-11-01

    Failure of the hypothalamus-pituitary-adrenal (HPA) axis to habituate to repeated stress exposure is related with adverse health outcomes, but our knowledge of predictors of non-habituation is limited. Rumination, defined as repetitive and unwanted past-centered negative thinking, is related with exaggerated HPA axis stress responses and poor health outcomes. The aim of this study was to test whether post-stress rumination was related with non-habituation of cortisol to repeated stress exposure. Twenty-seven participants (n=13 females) were exposed to the Trier Social Stress Test (TSST) twice on consecutive afternoons. Post-stress rumination was measured after the first TSST, and HPA axis responses were assessed by measuring salivary cortisol 1 min before, and 1, 10, 20, 60, and 120 min after both TSSTs. Stress exposure induced HPA axis activation on both days, and this activation showed habituation indicated by lower responses to the second TSST (F=3.7, p=0.015). Post-stress rumination after the first TSST was associated with greater cortisol reactivity after the initial stress test (r=0.45, p<0.05) and with increased cortisol responses to the second TSST (r=0.51, p<0.01), indicating non-habituation, independently of age, sex, depressive symptoms, perceived life stress, and trait rumination. In summary, results showed that rumination after stress predicted non-habituation of HPA axis responses. This finding implicates rumination as one possible mechanism mediating maladaptive stress response patterns, and it might also offer a pathway through which rumination might lead to negative health outcomes.

  5. Chronic activation of NPFFR2 stimulates the stress-related depressive behaviors through HPA axis modulation.

    PubMed

    Lin, Ya-Tin; Liu, Tzu-Yu; Yang, Ching-Yao; Yu, Yu-Lian; Chen, Ting-Chun; Day, Yuan-Ji; Chang, Che-Chien; Huang, Guo-Jen; Chen, Jin-Chung

    2016-09-01

    Neuropeptide FF (NPFF) is a morphine-modulating peptide that regulates the analgesic effect of opioids, and also controls food consumption and cardiovascular function through its interaction with two cognate receptors, NPFFR1 and NPFFR2. In the present study, we explore a novel modulatory role for NPFF-NPFFR2 in stress-related depressive behaviors. In a mouse model of chronic mild stress (CMS)-induced depression, the expression of NPFF significantly increased in the hypothalamus, hippocampus, medial prefrontal cortex (mPFC) and amygdala. In addition, transgenic (Tg) mice over-expressing NPFFR2 displayed clear depression and anxiety-like behaviors with hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis, reduced expression of glucocorticoid receptor (GR) and neurogenesis in the hippocampus. Furthermore, acute treatment of NPFFR2 agonists in wild-type (WT) mice enhanced the activity of the HPA axis, and chronic administration resulted in depressive and anxiety-like behaviors. Chronic stimulation of NPFFR2 also decreased the expression of hippocampal GR and led to persistent activation of the HPA axis. Strikingly, bilateral intra-paraventricular nucleus (PVN) injection of NPFFR2 shRNA predominately inhibits the depressive-like behavior in CMS-exposed mice. Antidepressants, fluoxetine and ketamine, effectively relieved the depressive behaviors of NPFFR2-Tg mice. We speculate that persistent NPFFR2 activation, in particular in the hypothalamus, up-regulates the HPA axis and results in long-lasting increases in circulating corticosterone (CORT), consequently damaging hippocampal function. This novel role of NPFFR2 in regulating the HPA axis and hippocampal function provides a new avenue for combating depression and anxiety-like disorder. PMID:27243477

  6. Evidence for a Role of Adolescent Endocannabinoid Signaling in Regulating HPA Axis Stress Responsivity and Emotional Behavior Development.

    PubMed

    Lee, Tiffany T-Y; Gorzalka, Boris B

    2015-01-01

    Adolescence is a period characterized by many distinct physical, behavioral, and neural changes during the transition from child- to adulthood. In particular, adolescent neural changes often confer greater plasticity and flexibility, yet with this comes the potential for heightened vulnerability to external perturbations such as stress exposure or recreational drug use. There is substantial evidence to suggest that factors such as adolescent stress exposure have longer lasting and sometimes more deleterious effects on an organism than stress exposure during adulthood. Moreover, the adolescent neuroendocrine response to stress exposure is different from that of adults, suggesting that further maturation of the adolescent hypothalamic-pituitary-adrenal (HPA) axis is required. The endocannabinoid (eCB) system is a potential candidate underlying these age-dependent differences given that it is an important regulator of the adult HPA axis and neuronal development. Therefore, this review will focus on (1) the functionality of the adolescent HPA axis, (2) eCB regulation of the adult HPA axis, (3) dynamic changes in eCB signaling during the adolescent period, (4) the effects of adolescent stress exposure on the eCB system, and (5) modulation of HPA axis activity and emotional behavior by adolescent cannabinoid treatment. Collectively, the emerging picture suggests that the eCB system mediates interactions between HPA axis stress responsivity, emotionality, and maturational stage. These findings may be particularly relevant to our understanding of the development of affective disorders and the risks of adolescent cannabis consumption on emotional health and stress responsivity. PMID:26638764

  7. Evidence for a Role of Adolescent Endocannabinoid Signaling in Regulating HPA Axis Stress Responsivity and Emotional Behavior Development.

    PubMed

    Lee, Tiffany T-Y; Gorzalka, Boris B

    2015-01-01

    Adolescence is a period characterized by many distinct physical, behavioral, and neural changes during the transition from child- to adulthood. In particular, adolescent neural changes often confer greater plasticity and flexibility, yet with this comes the potential for heightened vulnerability to external perturbations such as stress exposure or recreational drug use. There is substantial evidence to suggest that factors such as adolescent stress exposure have longer lasting and sometimes more deleterious effects on an organism than stress exposure during adulthood. Moreover, the adolescent neuroendocrine response to stress exposure is different from that of adults, suggesting that further maturation of the adolescent hypothalamic-pituitary-adrenal (HPA) axis is required. The endocannabinoid (eCB) system is a potential candidate underlying these age-dependent differences given that it is an important regulator of the adult HPA axis and neuronal development. Therefore, this review will focus on (1) the functionality of the adolescent HPA axis, (2) eCB regulation of the adult HPA axis, (3) dynamic changes in eCB signaling during the adolescent period, (4) the effects of adolescent stress exposure on the eCB system, and (5) modulation of HPA axis activity and emotional behavior by adolescent cannabinoid treatment. Collectively, the emerging picture suggests that the eCB system mediates interactions between HPA axis stress responsivity, emotionality, and maturational stage. These findings may be particularly relevant to our understanding of the development of affective disorders and the risks of adolescent cannabis consumption on emotional health and stress responsivity.

  8. Vulnerability to Stroke: Implications of Perinatal Programming of the Hypothalamic-Pituitary-Adrenal Axis

    PubMed Central

    Craft, Tara K. S.; DeVries, A. Courtney

    2009-01-01

    Chronic stress is capable of exacerbating each major, modifiable, endogenous risk factor for cerebrovascular and cardiovascular disease. Indeed, exposure to stress can increase both the incidence and severity of stroke, presumably through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Now that characterization of the mechanisms underlying epigenetic programming of the HPA axis is well underway, there has been renewed interest in examining the role of early environment on the evolution of health conditions across the entire lifespan. Indeed, neonatal manipulations in rodents that reduce stress responsivity, and subsequent life-time exposure to glucocorticoids, are associated with a reduction in the development of neuroendocrine, neuroanatomical, and cognitive dysfunctions that typically progress with age. Although improved day to day regulation of the HPA axis also may be accompanied by a decrease in stroke risk, evidence from rodent studies suggest that an associated cost could be increased susceptibility to inflammation and neuronal death in the event that a stroke does occur and the individual is exposed to persistently elevated corticosteroids. Given its importance in regulation of health and disease states, any long-term modulation of the HPA axis is likely to be associated with both benefits and potential risks. The goals of this review article are to examine (1) the clinical and experimental data suggesting that neonatal experiences can shape HPA axis regulation, (2) the influence of stress and the HPA axis on stroke incidence and severity, and (3) the potential for neonatal programming of the HPA axis to impact adult cerebrovascular health. PMID:20057937

  9. Functional characterization of the hypothalamic-pituitary-adrenal axis of the Wistar Audiogenic Rat (WAR) strain.

    PubMed

    Umeoka, Eduardo H L; Garcia, Sérgio Britto; Antunes-Rodrigues, José; Elias, Lucila L K; Garcia-Cairasco, Norberto

    2011-03-24

    The Wistar Audiogenic Rat (WAR) strain is a genetic model of sound-induced reflex epilepsy which was selected starting from audiogenic seizures susceptible Wistar rats. Wistar resistant rats were used as WAR's control in this study. In the acute situation, audiogenic seizures (AS) in WARs mimic tonic-clonic seizures and, in the chronic protocol, mimic temporal lobe epilepsy. AS have been shown to evoke neuroendocrine responses; however, the hypothalamic-pituitary-adrenal activity in the WAR has not been established. The aim of this study was to evaluate the hypothalamic-pituitary-adrenal axis (HPA) responses to exogenous ACTH stimulation (8 ng/rat), fifteen minute restraint stress and circadian variation (8 am and 8 pm) under rest conditions in these animals through plasma measurements of ACTH and corticosterone concentrations. We also measured the body weight from birth to the 9th week of life and determined adrenal gland weight. We found that WARs are smaller than Wistar and presented a higher adrenal gland weight with a higher level of corticosterone release after intravenous ACTH injection. They also showed altered HPA axis circadian rhythms and responses to restraint stress. Our data indicate that, despite the lower body weight, WARs have increased adrenal gland weight associated with enhanced pituitary and adrenal responsiveness after HPA axis stimulation. Thus, we propose WARs as a model to study stress-epilepsy interactions and epilepsy-neuropsychiatry comorbidities.

  10. Adrenal axis activation by chronic social stress fails to inhibit gonadal function in male rats.

    PubMed

    Lemaire, V; Taylor, G T; Mormède, P

    1997-11-01

    Stress in males via the hypothalamic-pituitary-adrenal (HPA) axis may set into motion varied physiological alterations, including dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. However, the influence of the HPA on the HPG axis may not always be inhibitory. Presence or absence of stimuli of sexual significance that typically activates the HPG axis may alter the influence of the adrenal axis on gonadal axes. In this project, we used male rats and chronic social stimulation that included brief or extended periods with female rats to examine HPA-HPG axes interactions. In experiment 1, we used intact males and a 'chronic social stress' paradigm developed in our previous research that induces social instability by daily changing the membership of group-housed males with females. Thymus weight was reduced and corticosterone levels were marginally increased by chronic social stress, indicating a HPA axis hyperactivity. The HPG axis was also activated as shown by the increased weight of the androgen-sensitive sex structures. These results indicate that when these two axes are stimulated together, neither interferes with nor suppresses activities of the other. Implants of corticosterone pellets to adrenalectomized animals that maintained constant, high corticosterone levels failed to reverse the gonadal hyperactivity induced by sexual stimulation. In a second experiment, we studied the influence of different intensity of sexual stimulations on HPA-HPG axes interactions. Increased corticosterone levels and adrenal weight, indicating a HPA hyperactivity, failed to inhibit HPG hyperactivity as measured by the increased sexual organs weight, whatever the sexual intensity of the stimulation. This work demonstrates that the gonadal axis is freed from suppression when sexual stimulation occurs together with stress. The general conclusion is that the nature of complex social settings is important in determining interactions between the two neuroendocrine axes.

  11. Burnout Is Associated with Reduced Parasympathetic Activity and Reduced HPA Axis Responsiveness, Predominantly in Males

    PubMed Central

    de Vente, Wieke; van Amsterdam, Jan G. C.; Olff, Miranda; Kamphuis, Jan H.; Emmelkamp, Paul M. G.

    2015-01-01

    There is mounting evidence that burnout is a risk factor for cardiovascular disease (CVD). Stress-related dysregulation of the sympathetic and parasympathetic system and the hypothalamic pituitary adrenal (HPA) axis may explain the enhanced risk for CVD. To test this hypothesis, 55 patients (34 males and 21 females) with burnout on sickness absence and 40 healthy participants (16 males and 24 females) were exposed to a psychosocial stressor consisting of mental arithmetic and public speech. Physiological variables (i.e., blood pressure, heart rate, cardiac output, vascular resistance, cortisol, and alpha-amylase) were measured. Basal levels, reactivity, and recovery were compared between groups. In male patients, baseline systolic blood pressure was higher, whereas basal alpha-amylase and cortisol reactivity were lower than in healthy males. In female patients, a tendency for lower basal cortisol was found as compared to healthy females. Furthermore, reduced basal heart rate variability and a trend for elevated basal cardiac output were observed in both male and female patients. Burnout is characterised by dysregulation of the sympathetic and parasympathetic system and the HPA axis, which was more pronounced in males than in females. This study further supports burnout as being a risk factor for CVD through dysregulation of the sympathetic and parasympathetic system and the HPA axis. PMID:26557670

  12. Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome.

    PubMed

    Weinberg, J; Sliwowska, J H; Lan, N; Hellemans, K G C

    2008-04-01

    Prenatal exposure to alcohol has adverse effects on offspring neuroendocrine and behavioural functions. Alcohol readily crosses the placenta, thus directly affecting developing foetal endocrine organs. In addition, alcohol-induced changes in maternal endocrine function can disrupt the normal hormonal interactions between the pregnant female and foetal systems, altering the normal hormone balance and, indirectly, affecting the development of foetal metabolic, physiological and endocrine functions. The present review focuses on the adverse effects of prenatal alcohol exposure on offspring neuroendocrine function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis, a key player in the stress response. The HPA axis is highly susceptible to programming during foetal and neonatal development. Here, we review data demonstrating that alcohol exposure in utero programmes the foetal HPA axis such that HPA tone is increased throughout life. Importantly, we show that, although alterations in HPA responsiveness and regulation are robust phenomena, occurring in both male and female offspring, sexually dimorphic effects of alcohol are frequently observed. We present updated findings on possible mechanisms underlying differential effects of alcohol on male and female offspring, with special emphasis on effects at different levels of the HPA axis, and on modulatory influences of the hypothalamic-pituitary-gonadal hormones and serotonin. Finally, possible mechanisms underlying foetal programming of the HPA axis, and the long-term implications of increased exposure to endogenous glucocorticoids for offspring vulnerability to illnesses or disorders later in life are discussed.

  13. HPA-axis stress reactivity in youth depression: evidence of impaired regulatory processes in depressed boys.

    PubMed

    Lopez-Duran, Nestor L; McGinnis, Ellen; Kuhlman, Kate; Geiss, Elisa; Vargas, Ivan; Mayer, Stefanie

    2015-01-01

    Given the link between youth depression and stress exposure, efforts to identify related biomarkers have involved examinations of stress regulation systems, including the hypothalamic-pituitary-adrenal (HPA) axis. Despite these vast efforts, the underlying mechanisms at play, as well as factors that may explain heterogeneity of past findings, are not well understood. In this study, we simultaneously examined separate components of the HPA-axis response (e.g. activation intensity, peak levels, recovery) to the Socially Evaluated Cold-Pressor Test in a targeted sample of 115 youth (age 9-16), recruited to overrepresent youth with elevated symptoms of depression. Among youth who displayed a cortisol response to the task, depression symptoms were associated with higher peak responses but not greater rate of activation or recovery in boys only. Among those who did not respond to the task, depression symptoms were associated with greater cortisol levels throughout the visit in boys and girls. Results suggest that depression symptoms are associated with a more prolonged activation of the axis and impaired recovery to psychosocial stressors primarily in boys. We discussed two potential mechanistic explanations of the link between depression symptoms and the duration of activation: (1) inhibitory shift (i.e. point at which the ratio of inhibitory and excitatory input into the axis shifts from greater excitatory to greater inhibitory input) or (2) inhibitory threshold (i.e. level of cortisol exposure required to activate the axis' feedback inhibition system).

  14. Activation of the hypothalamic-pituitary-adrenal axis in lithium-induced conditioned taste aversion learning.

    PubMed

    Jahng, Jeong Won; Lee, Jong-Ho

    2015-12-01

    Intraperitoneal injections (ip) of lithium chloride at large doses induce c-Fos expression in the brain regions implicated in conditioned taste aversion (CTA) learning, and also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase the plasma corticosterone levels in rats. A pharmacologic treatment blunting the lithium-induced c-Fos expression in the brain regions, but not the HPA axis activation, induced CTA formation. Synthetic glucocorticoids at conditioning, but not glucocorticoid antagonist, attenuated the lithium-induced CTA acquisition. The CTA acquisition by ip lithium was not affected by adrenalectomy regardless of basal corticosterone supplement, but the extinction was delayed in the absence of basal corticosterone. Glucocorticoids overloading delayed the extinction memory formation of lithium-induced CTA. ip lithium consistently induced the brain c-Fos expression, the HPA activation and CTA formation regardless of the circadian activation of the HPA axis. Intracerebroventricular (icv) injections of lithium at day time also increased the brain c-Fos expression, activated the HPA axis and induced CTA acquisition. However, icv lithium at night, when the HPA axis shows its circadian activation, did not induce CTA acquisition nor activate the HPA axis, although it increased the brain c-Fos expression. These results suggest that the circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA learning in rats, and the HPA axis activation may be necessary for the central effect of lithium in CTA formation. Also, glucocorticoids may be required for a better extinction; however, increased glucocorticoids hinder both the acquisition and the extinction of lithium-induced CTA.

  15. Early-Life Stress, HPA Axis Adaptation, and Mechanisms Contributing to Later Health Outcomes

    PubMed Central

    Maniam, Jayanthi; Antoniadis, Christopher; Morris, Margaret J.

    2014-01-01

    Stress activates the hypothalamic–pituitary–adrenal (HPA) axis, which then modulates the degree of adaptation and response to a later stressor. It is known that early-life stress can impact on later health but less is known about how early-life stress impairs HPA axis activity, contributing to maladaptation of the stress–response system. Early-life stress exposure (either prenatally or in the early postnatal period) can impact developmental pathways resulting in lasting structural and regulatory changes that predispose to adulthood disease. Epidemiological, clinical, and experimental studies have demonstrated that early-life stress produces long term hyper-responsiveness to stress with exaggerated circulating glucocorticoids, and enhanced anxiety and depression-like behaviors. Recently, evidence has emerged on early-life stress-induced metabolic derangements, for example hyperinsulinemia and altered insulin sensitivity on exposure to a high energy diet later in life. This draws our attention to the contribution of later environment to disease vulnerability. Early-life stress can alter the expression of genes in peripheral tissues, such as the glucocorticoid receptor and 11-beta hydroxysteroid dehydrogenase (11β-HSD1). We propose that interactions between altered HPA axis activity and liver 11β-HSD1 modulates both tissue and circulating glucocorticoid availability, with adverse metabolic consequences. This review discusses the potential mechanisms underlying early-life stress-induced maladaptation of the HPA axis, and its subsequent effects on energy utilization and expenditure. The effects of positive later environments as a means of ameliorating early-life stress-induced health deficits, and proposed mechanisms underpinning the interaction between early-life stress and subsequent detrimental environmental exposures on metabolic risk will be outlined. Limitations in current methodology linking early-life stress and later health outcomes will also be

  16. Genetic variation of the cutaneous HPA axis: an analysis of UVB-induced differential responses.

    PubMed

    Skobowiat, Cezary; Nejati, Reza; Lu, Lu; Williams, Robert W; Slominski, Andrzej T

    2013-11-01

    Mammalian skin incorporates a local equivalent of the hypothalamic-pituitary-adrenal (HPA) axis that is critical in coordinating homeostatic responses against external noxious stimuli. Ultraviolet radiation B (UVB) is a skin-specific stressor that can activate this cutaneous HPA axis. Since C57BL/6 (B6) and DBA/2J (D2) strains of mice have different predispositions to sensorineural pathway activation, we quantified expression of HPA axis components at the gene and protein levels in skin incubated ex vivo after UVB or sham irradiation. Urocortin mRNA was up-regulated after all doses of UVB with a maximum level at 50 mJ/cm(2) after 12h for D2 and at 200 mJ/cm(2) after 24h for B6. Proopiomelanocortin mRNA was enhanced after 6h with the peak after 12h and at 200 mJ/cm(2) for both genotypes of mice. ACTH levels in tissue and media increased after 24h in B6 but not in D2. UVB stimulated β-endorphin expression was higher in D2 than in B6. Melanocortin receptor 2 mRNA was stimulated by UVB in a dose-dependent manner, with a peak at 200 mJ/cm(2) after 12h for both strains. The expression of Cyp11a1 mRNA - a key mitochondrial P450 enzyme in steroidogenesis, was stimulated at all doses of UVB irradiation, with the most pronounced effect after 12-24h. UVB radiation caused, independently of genotype, a dose-dependent increase in corticosterone production in the skin, mainly after 24h of histoculture. Thus, basal and UVB stimulated expression of the cutaneous HPA axis differs as a function of genotype: D2 responds to UVB earlier and with higher amplitude than B6, while B6 shows prolonged (up to 48 h) stress response to a noxious stimulus such as UVB. PMID:23962689

  17. Immune Function and HPA Axis Activity in Free-Ranging Rhesus Macaques

    PubMed Central

    Hoffman, Christy L.; Higham, James P.; Heistermann, Michael; Coe, Christopher L.; Prendergast, Brian J.; Maestripieri, Dario

    2011-01-01

    In mammals, the hypothalamic-pituitary-adrenal (HPA) axis and immune system play an important role in the maintenance of homeostasis. Dysregulation of either system resulting, for example, from psychosocial or reproductive stress increases susceptibility to disease and mortality risk, especially in aging individuals. In a study of free-ranging rhesus macaques, we examined how female age, reproductive state, social rank, and body condition influence (i) aspects of cytokine biology (plasma concentrations of interleukin-1 receptor antagonist (IL-1ra), IL-6 and IL-8), and (ii) HPA axis activity (plasma and fecal glucocorticoid levels). We also assessed individual differences in cytokine and hormone concentrations over time to determine their consistency and to investigate relations between these two indicators of physiological regulation and demand. Female monkeys showed marked increases in HPA axis activity during pregnancy and lactation, and increased circulating levels of IL-1ra with advancing age. Inter-individual differences in IL-1ra and IL-8 were consistent over successive years, suggesting that both are stable, trait-like characteristics. Furthermore, the concentrations of fecal glucocorticoid hormones in non-pregnant, non-lactating females were correlated with their plasma cortisol and IL-8 concentrations. Some individuals showed permanently elevated cytokine levels or HPA axis activity, or a combination of the two, suggesting chronic stress or disease. Our results enhance our understanding of within- and between-individual variation in cytokine levels and their relationship with glucocorticoid hormones in free-ranging primates. These findings can provide the basis for future research on stress and allostatic load in primates. PMID:21635909

  18. Genetic variation of the cutaneous HPA axis: An analysis of UVB-induced differential responses

    PubMed Central

    Skobowiat, Cezary; Nejati, Reza; Lu, Lu; Williams, Robert W.; Slominski, Andrzej T.

    2013-01-01

    Mammalian skin incorporates a local equivalent of the hypothalamic-pituitary-adrenal (HPA) axis that is critical in coordinating homeostatic responses against external noxious stimuli. Ultraviolet radiation B (UVB) is a skin-specific stressor that can activate this cutaneous HPA axis. Since C57BL/6 (B6) and DBA/2J (D2) strains of mice have different predispositions to sensorineural pathway activation, we quantified expression of HPA axis components at the gene and protein levels in skin incubated ex vivo after UVB or sham irradiation. Urocortin mRNA was up-regulated after all doses of UVB with a maximum level at 50 mJ/cm2 after 12 h for D2 and at 200 mJ/cm2 after 24 h for B6. Proopiomelanocortin mRNA was enhanced after 6 h with the peak after 12 h and at 200 mJ/cm2 for both genotypes of mice. ACTH levels in tissue and media increased after 24 h in B6 but not in D2. UVB stimulated β-endorphin expression was higher in D2 than B6. Melanocortin receptor 2 mRNA was stimulated by UVB in a dose-dependent manner, with a peak at 200 mJ/cm2 after 12 h for both strains. The expression of Cyp11a1 mRNA — a key mitochondrial P450 enzyme in steroidogenesis, was stimulated at all doses of UVB irradiation, with the most pronounced effect after 12–24 h. UVB radiation caused, independently of genotype, a dose-dependent increases in corticosterone production in the skin, mainly after 24 h of histoculture. Thus, basal and UVB stimulated expression of the cutaneous HPA axis differs as a function of genotype: D2 responds to UVB earlier and with higher amplitude than B6, while B6 shows prolonged (up to 48 h) stress response to a noxious stimulus such as UVB. PMID:23962689

  19. Effects of orchidectomy and testosterone replacement on mouse pyrrolidone carboxypeptidase activity in the HPA axis.

    PubMed

    García-López, M J; Martínez-Martos, J M; Mayas, M D; Carrera, M P; Ramírez-Expósito, M J

    2004-03-01

    Pyrrolidone carboxypeptidase, also known as pyroglutamyl aminopeptidase, removes pyroglutamyl terminal residues from biologically active peptides such as thyrotropin-releasing hormone. The aim of the present work was to study the influence of orchidectomy and testosterone replacement on soluble (pyrrolidone carboxypeptidase type I) and membrane-bound (pyrrolidone carboxypeptidase type II) activities in the hypothalamus-pituitary-adrenal axis. Forty male mice (Balb/C) were distributed into five groups: sham-operated controls, orchidectomized, and orchidectomized treated with increasing doses of testosterone in each group (3, 6 and 12 mg/kg). In the hypothalamus, orchidectomy increased pyrrolidone carboxypeptidase type I, whereas the highest dose of testosterone returned this activity to control levels. In the pituitary, neither pyrrolidone carboxypeptidase type I nor type II activities changed after orchidectomy, although both activities increased after administration of testosterone in both cases. On the other hand, orchidectomy increased pyrrolidone carboxypeptidase type I and type II activities in adrenal glands, while testosterone replacement returned it to control levels. These results suggest that testosterone differentially modulates pyrrolidone carboxypeptidase type I and type II activities, and therefore also their endogenous substrate regulation. Thus, the influence of sex hormones in the physiology of the HPA axis through the modulation of the Pyrrolidone carboxypeptidase type I and type II activities is of great importance on stress and neuropathology associated with HPA dysfunction

  20. Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function.

    PubMed

    Fan, Ying; Ma, Lian; Pippins, Jennifer; Limb, Susan; Xu, Yun; Sahajwalla, Chandrahas G

    2014-10-01

    In part I of this review, an overview of the designs of hypothalamic-pituitary-adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study.

  1. HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats.

    PubMed

    Kosten, Therese A; Ambrosio, Emilio

    2002-01-01

    Much research supports a link between stress and its concomitant hypothalamic-pituitary-adrenal (HPA) axis responses with behavioral sensitivity to psychoactive drugs. Our research demonstrates that Lewis inbred rats more readily acquire drug self-administration than Fischer 344 (F344) inbred rats and, compared to this strain, Lewis rats have hyporesponsive HPA axis responses to stress exposure. This association appears to conflict with investigations using outbred rats and suggests that the relationship between drug sensitivity and HPA axis responsiveness is more complicated than originally thought. It is essential to better understand this relationship because of its relevance to vulnerability and relapse to drug abuse. Thus, this paper reviews the literature in which these two inbred strains have been compared. We discuss strain differences in HPA axis function, in characteristics of the mesolimbic dopamine system, and in behaviors thought to reflect emotionality. Strain differences in unconditioned and conditioned effects of psychoactive drugs are then reviewed. Next, we discuss the possible role of sex and gonadal hormones on responsiveness to psychoactive drugs in these strains. Finally, a comparison of results obtained from these strains to three other comparator groups (e.g., high and low responders) suggests that a non-monotonic relationship between behavioral sensitivity to drugs and HPA axis responsiveness can explain much of the discrepancies in the literature.

  2. Prenatal xenobiotic exposure and intrauterine hypothalamus-pituitary-adrenal axis programming alteration.

    PubMed

    Zhang, Chong; Xu, Dan; Luo, Hanwen; Lu, Juan; Liu, Lian; Ping, Jie; Wang, Hui

    2014-11-01

    The hypothalamic-pituitary-adrenal (HPA) axis is one of the most important neuroendocrine axes and plays an important role in stress defense responses before and after birth. Prenatal exposure to xenobiotics, including environmental toxins (such as smoke, sulfur dioxide and carbon monoxide), drugs (such as synthetic glucocorticoids), and foods and beverage categories (such as ethanol and caffeine), affects fetal development indirectly by changing the maternal status or damaging the placenta. Certain xenobiotics (such as caffeine, ethanol and dexamethasone) may also affect the fetus directly by crossing the placenta into the fetus due to their lipophilic properties and lower molecular weights. All of these factors probably result in intrauterine programming alteration of the HPA axis, which showed a low basal activity but hypersensitivity to chronic stress. These alterations will, therefore, increase the susceptibility to adult neuropsychiatric (such as depression and schizophrenia) and metabolic diseases (such as hypertension, diabetes and non-alcoholic fatty liver disease). The "over-exposure of fetuses to maternal glucocorticoids" may be the main initiation factor by which the fetal HPA axis programming is altered. Meantime, xenobiotics can directly induce abnormal epigenetic modifications and expression on the important fetal genes (such as hippocampal glucocorticoid receptor, adrenal steroidogenic acute regulatory protein, et al) or damage by in situ oxidative metabolism of fetal adrenals, which may also be contributed to the programming alteration of fetal HPA axis.

  3. Enhancing offspring hypothalamic-pituitary-adrenal (HPA) regulation via systematic novelty exposure: the influence of maternal HPA function.

    PubMed

    Dinces, Sarah M; Romeo, Russell D; McEwen, Bruce S; Tang, Akaysha C

    2014-01-01

    In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother's ability to mount a rapid corticosterone (CORT) response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring hypothalamic-pituitary-adrenal (HPA) regulation. Using a 2 × 2 within-litter design, one half of each litter were exposed to a relatively novel non-home environment for 3-min (Neo_Novel) daily during infancy (PND 1-21) and the other half of the litter remained in the home cage (Neo_Home); we further exposed half of these two groups to early adulthood (PND 54-63) novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting CORT (CORTB) and the ability to mount a large rapid CORT response (CORTE) to the onset of an acute stressor. Assessment of adult offspring's ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring's ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent upon the

  4. Hypothalamic-pituitary-adrenal axis function in ankylosing spondylitis

    PubMed Central

    Imrich, R; Rovensky, J; Zlnay, M; Radikova, Z; Macho, L; Vigas, M; Koska, J

    2004-01-01

    Objective: To assess basal function and responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis in patients with ankylosing spondylitis during dynamic testing. Methods: Insulin induced hypoglycaemia (IIH) (Actrapid HM 0.1 IU/kg, as intravenous bolus) was induced in 17 patients and 11 healthy controls matched for age, sex, and body mass index. Concentrations of glucose, adrenocorticotrophic hormone (ACTH), cortisol, insulin, dehydroepiandrosterone sulphate (DHEAS), 17α-hydroxyprogesterone, interleukin 6 (IL-6), and tumour necrosis factor α (TNFα) were determined in plasma. Results: Comparable basal cortisol levels were found in the two groups, with a trend to be lower in ankylosing spondylitis. In the ankylosing spondylitis group, there were higher concentrations of IL-6 (mean (SEM): 16.6 (2.8) pg/ml v 1.41 (0.66) pg/ml in controls; p<0.001) and TNFα (8.5 (1.74) pg/ml v 4.08 (0.42) pg/ml in controls; p<0.01). Glucose, insulin, ACTH, DHEAS, and 17α-hydroxyprogesterone did not differ significantly from control. The IIH test was carried out successfully in 11 of the 17 patients with ankylosing spondylitis, and the ACTH and cortisol responses were comparable with control. General linear modelling showed a different course of glycaemia (p = 0.041) in the ankylosing spondylitis patients who met the criteria for a successful IIH test compared with the controls. Conclusions: The results suggest there is no difference in basal HPA axis activity and completely preserved responsiveness of the HPA axis in patients with ankylosing spondylitis. The interpretation of the different course of glycaemia during IIH in ankylosing spondylitis requires further investigation. PMID:15140773

  5. Resetting the dynamic range of hypothalamic-pituitary-adrenal axis stress responses through pregnancy.

    PubMed

    Brunton, P J

    2010-11-01

    The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the neuroendocrine response to stress. Dynamic changes in HPA axis regulation and hence HPA responsivity occur over the lifetime of an animal. This article focuses on two extremes of the spectrum. The first occurs naturally during pregnancy when stress responses are dampened. The second, at the opposite end of the scale, occurs in offspring of mothers who were exposed to stress during pregnancy and display exaggerated HPA axis stress responses. Reduced glucocorticoid output in response to stress in pregnancy may have important consequences for conserving energy supply to the foetus(es), in modulating immune system adaptations and in protecting against adverse foetal programming by glucocorticoids. Understanding the mechanisms underpinning this adaptation in pregnancy may provide insights for manipulating HPA axis responsiveness in later life, particularly in the context of resetting HPA axis hyperactivity associated with prenatal stress exposure, which may underlie several major pathologies, including cardiovascular disease, diabetes mellitus type 2, obesity, cognitive decline and mood disorders.

  6. The minimal model of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Vinther, Frank; Andersen, Morten; Ottesen, Johnny T

    2011-10-01

    This paper concerns ODE modeling of the hypothalamic-pituitary- adrenal axis (HPA axis) using an analytical and numerical approach, combined with biological knowledge regarding physiological mechanisms and parameters. The three hormones, CRH, ACTH, and cortisol, which interact in the HPA axis are modeled as a system of three coupled, nonlinear differential equations. Experimental data shows the circadian as well as the ultradian rhythm. This paper focuses on the ultradian rhythm. The ultradian rhythm can mathematically be explained by oscillating solutions. Oscillating solutions to an ODE emerges from an unstable fixed point with complex eigenvalues with a positive real parts and a non-zero imaginary parts. The first part of the paper describes the general considerations to be obeyed for a mathematical model of the HPA axis. In this paper we only include the most widely accepted mechanisms that influence the dynamics of the HPA axis, i.e. a negative feedback from cortisol on CRH and ACTH. Therefore we term our model the minimal model. The minimal model, encompasses a wide class of different realizations, obeying only a few physiologically reasonable demands. The results include the existence of a trapping region guaranteeing that concentrations do not become negative or tend to infinity. Furthermore, this treatment guarantees the existence of a unique fixed point. A change in local stability of the fixed point, from stable to unstable, implies a Hopf bifurcation; thereby, oscillating solutions may emerge from the model. Sufficient criteria for local stability of the fixed point, and an easily applicable sufficient criteria guaranteeing global stability of the fixed point, is formulated. If the latter is fulfilled, ultradian rhythm is an impossible outcome of the minimal model and all realizations thereof. The second part of the paper concerns a specific realization of the minimal model in which feedback functions are built explicitly using receptor dynamics. Using

  7. Sex and stress steroids in adolescence: Gonadal regulation of the hypothalamic-pituitary-adrenal axis in the rat.

    PubMed

    Green, Matthew R; McCormick, Cheryl M

    2016-08-01

    This review provides an overview of the current understanding of the role of the hypothalamic-pituitary-gonadal (HPG) axis in regulating the hypothalamic-pituitary-adrenal (HPA) axis response to stressors. HPA function is influenced by both organizational (programming) and activational effects of gonadal hormones. Typically, in adult rats, estradiol increases and androgens decrease the HPA response to stressors, thereby contributing to sex differences in HPA function, and sensitivity of the HPA axis to gonadal steroids is in part determined by exposure to these hormones in early development. Although developmental differences in HPA function are well characterized, the extent to which gonadal steroids contribute to age differences in HPA function is not well understood. Deficits in the understanding of the relationships between the HPA and HPG axes are greatest for the adolescent period of development. The critical outstanding questions are, when do gonadal hormones begin to regulate HPA function in adolescence, and what mechanisms precipitate change in sensitivity of the HPA axis to the HPG axis at this stage of life.

  8. Sex and stress steroids in adolescence: Gonadal regulation of the hypothalamic-pituitary-adrenal axis in the rat.

    PubMed

    Green, Matthew R; McCormick, Cheryl M

    2016-08-01

    This review provides an overview of the current understanding of the role of the hypothalamic-pituitary-gonadal (HPG) axis in regulating the hypothalamic-pituitary-adrenal (HPA) axis response to stressors. HPA function is influenced by both organizational (programming) and activational effects of gonadal hormones. Typically, in adult rats, estradiol increases and androgens decrease the HPA response to stressors, thereby contributing to sex differences in HPA function, and sensitivity of the HPA axis to gonadal steroids is in part determined by exposure to these hormones in early development. Although developmental differences in HPA function are well characterized, the extent to which gonadal steroids contribute to age differences in HPA function is not well understood. Deficits in the understanding of the relationships between the HPA and HPG axes are greatest for the adolescent period of development. The critical outstanding questions are, when do gonadal hormones begin to regulate HPA function in adolescence, and what mechanisms precipitate change in sensitivity of the HPA axis to the HPG axis at this stage of life. PMID:26851306

  9. Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis

    NASA Astrophysics Data System (ADS)

    Čupić, Željko; Marković, Vladimir M.; Maćešić, Stevan; Stanojević, Ana; Damjanović, Svetozar; Vukojević, Vladana; Kolar-Anić, Ljiljana

    2016-03-01

    Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.

  10. Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Čupić, Željko; Marković, Vladimir M; Maćešić, Stevan; Stanojević, Ana; Damjanović, Svetozar; Vukojević, Vladana; Kolar-Anić, Ljiljana

    2016-03-01

    Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamic-pituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations. PMID:27036189

  11. The hypothalamic-pituitary-adrenal axis and the female reproductive system.

    PubMed

    Magiakou, M A; Mastorakos, G; Webster, E; Chrousos, G P

    1997-06-17

    The hypothalamic-pituitary-adrenal (HPA) axis and the female reproductive system are intertwined and exhibit a complex relationship. Thus, the HPA axis exerts profound, mostly inhibitory effects, on the reproductive axis, with corticotropin-releasing hormone (CRH) and CRH-induced propiomelanocortin peptides inhibiting hypothalamic GnRH secretion, and with glucocorticoids inhibiting pituitary LH and ovarian estrogen and progesterone secretion and rendering estrogen-target tissues, such as the endometrium, resistant to the gonadal steroid. These effects of the HPA axis are responsible for the "hypothalamic" amenorrhea of stress, depression and eating disorders, and the hypogonadism of Cushing's syndrome. Conversely, estrogen directly stimulates the CRH gene, which may explain the slight hypercortisolism of females and the preponderance of depressive, anxiety, and eating disorders, as well as Cushing's disease in women. Interestingly, several components of the HPA axis and their receptors are present in reproductive tissues, as autocoid regulators of their various functions. These include ovarian and endometrial CRH, which may participate in the inflammatory processes of the ovary, that is, ovulation and luteolysis, and of the endometrium, that is, implantation and menstruation. Finally, the hypercortisolism of the latter half of pregnancy can be explained by high levels of placenta CRH in plasma. This hypercortisolism causes a transient adrenal suppression in the postpartum period, which may explain the postpartum blues/depression and autoimmune phenomena of this period.

  12. Cerebrovascular Cyclooxygenase-1 Expression, Regulation and Role in HPA Axis Activation by Inflammatory Stimuli

    PubMed Central

    Bueno, Borja García; Serrats, Jordi; Sawchenko, Paul E.

    2012-01-01

    Systemic injection of lipopolysaccharide (LPS) is a widely used model of immune/inflammatory challenge, which can invoke a host of CNS responses, including activation of the hypothalamo-pituitary-adrenal (HPA) axis. Inducible vascular prostaglandin E2 (PGE2) synthesis by endothelial (ECs) and/or perivascular cells (PVCs; a macrophage-derived vascular cell type) is implicated in the engagement of HPA and other CNS responses, by virtue of their capacity to express cyclooxygenase-2 (COX-2) and microsomal PGE2 synthase-1. Evidence from genetic and pharmacologic studies also supports a role for the constitutively expressed cyclooxygenase isoform-1 (COX-1) in inflammation-induced activation of the HPA axis, though histochemical evidence to support relevant localization(s) and regulation of COX-1 expression is lacking. The present experiments fill this void in showing that COX-1 immunoreactivity (ir) and mRNA are detectable in identified PVCs and parenchymal microglia under basal conditions, and is robustly expressed in these and ECs 1-3 hr after intravenous injection of LPS (2 μg/kg). Confocal and electron microscopic analyses indicate distinct cellular/subcellular localizations of COX-1-ir in the three cell types. Interestingly, COX-1 expression is enhanced in ECs of brain PVC-depleted rats, supporting an anti-inflammatory role of the latter cell type. Functional involvement of COX-1 is indicated by the observation that central, but not systemic, pre-treatment with the selective COX-1 inhibitor, SC-560, attenuated the early phase of LPS-induced increases in adrenocorticotropin and corticosterone secretion. These findings support an involvement of COX-1 in bidirectional interplay between ECs and PVCs in initiating vascular PGE2, and downstream HPA response to proinflammatory challenges. PMID:19828811

  13. HPA axis genes may modulate the effect of childhood adversities on decision-making in suicide attempters.

    PubMed

    Guillaume, Sebastien; Perroud, Nader; Jollant, Fabrice; Jaussent, Isabelle; Olié, Emilie; Malafosse, Alain; Courtet, Philippe

    2013-02-01

    Decision-making impairment is found in several neuropsychiatric disorders, including suicidal behavior, and has been shown to be modulated by genes. On the other hand, early trauma have/has been associated with poor mental health outcome in adulthood, in interaction with genetic factors, possibly through sustained alterations in the hypothalamic-pituitary-adrenal axis (HPA axis). Here, we aimed to investigate the effect of childhood trauma and its interaction with HPA-axis related genes on decision-making abilities in adulthood among a sample of suicide attempters. The Iowa Gambling Task (IGT) was used to assess decision-making in 218 patients with a history of suicide attempt. Participant fulfilled the Childhood Trauma Questionnaire to report traumatic childhood experiences. Patients were genotyped for single-nucleotide polymorphisms within CRHR1 and CRHR2 genes. Patients with a history of sexual abuse had significantly lower IGT scores than non-sexually abused individuals. Polymorphisms within CRHR1 and CRHR2 genes interacted with both childhood sexual abuse and emotional neglect to influence IGT performance. In conclusion, childhood sexual abuse and emotional neglect may have long-term effects on decision-making through an interaction with key HPA axis genes. Even if these results need to be replicated in other sample, impaired decision-making may thus be the dimension through which child maltreatment, in interaction with HPA axis related genes, may have a sustained negative impact on adult mental health. PMID:23177644

  14. Characterization of the Hypothalamic-Pituitary-Adrenal-Axis in Familial Longevity under Resting Conditions

    PubMed Central

    Jansen, Steffy W.; Roelfsema, Ferdinand; Akintola, Abimbola A.; Oei, Nicole Y.; Cobbaert, Christa M.; Ballieux, Bart E.; van der Grond, Jeroen; Westendorp, Rudi G.; Pijl, Hanno; van Heemst, Diana

    2015-01-01

    Objective The hypothalamic-pituitary-adrenal (HPA)-axis is the most important neuro-endocrine stress response system of our body which is of critical importance for survival. Disturbances in HPA-axis activity have been associated with adverse metabolic and cognitive changes. Humans enriched for longevity have less metabolic and cognitive disturbances and therefore diminished activity of the HPA axis may be a potential candidate mechanism underlying healthy familial longevity. Here, we compared 24-h plasma ACTH and serum cortisol concentration profiles and different aspects of the regulation of the HPA-axis in offspring from long-lived siblings, who are enriched for familial longevity and age-matched controls. Design Case-control study within the Leiden Longevity study cohort consisting of 20 middle-aged offspring of nonagenarian siblings (offspring) together with 18 partners (controls). Methods During 24 h, venous blood was sampled every 10 minutes for determination of circulatory ACTH and cortisol concentrations. Deconvolution analysis, cross approximate entropy analysis and ACTH-cortisol-dose response modeling were used to assess, respectively, ACTH and cortisol secretion parameters, feedforward and feedback synchrony and adrenal gland ACTH responsivity. Results Mean (95% Confidence Interval) basal ACTH secretion was higher in male offspring compared to male controls (645 (324-1286) ngl/L/24 h versus 240 (120-477) ng/L/24 h, P = 0.05). Other ACTH and cortisol secretion parameters did not differ between offspring and controls. In addition, no significant differences in feedforward and feedback synchrony and adrenal gland ACTH responsivity were observed between groups. Conclusions These results suggest that familial longevity is not associated with major differences in HPA-axis activity under resting conditions, although modest, sex-specific differences may exist between groups that might be clinically relevant. PMID:26193655

  15. A Hyperresponsive HPA Axis May Confer Resilience Against Persistent Paclitaxel-Induced Mechanical Hypersensitivity.

    PubMed

    Kozachik, Sharon L; Page, Gayle G

    2016-05-01

    Paclitaxel (PAC) treatment is associated with persistent, debilitating neuropathic pain that affects the hands and feet. Female sex and biological stress responsivity are risk factors for persistent pain, but it is unclear whether these important biologically based factors confer risk for PAC-induced neuropathic pain. To determine the relative contributions of sex and hypothalamic-pituitary-adrenal (HPA)-axis stress responsivity to PAC-induced mechanical hypersensitivity, we employed a PAC protocol consisting of three, 2-week cycles of every-other-day doses of PAC 1 mg/kg versus saline (Week 1) and recovery (Week 2), totaling 42 days, in mature male and female Fischer 344, Lewis, and Sprague Dawley (SD) rats, known to differ in HPA axis stress responsivity. Mechanical sensitivity was operationalized using von Frey filaments, per the up-down method. Among PAC-injected rats, SD rats exhibited significantly greater mechanical hypersensitivity relative to accumulative PAC doses compared to Fischer 344 rats. Lewis rats were not significantly different in mechanical hypersensitivity from SD or Fischer 344 rats. At the end of the protocol, PAC-injected SD rats exhibited profound mechanical hypersensitivity, whereas the PAC-injected Fischer 344 rats appeared relatively resilient to the long-term effects of PAC and exhibited mechanical sensitivity that was not statistically different from their saline-injected counterparts. Sex differences were mixed and noted only early in the PAC protocol. Moderate HPA axis stress responsivity may confer additional risk for the painful effects of PAC. If these findings hold in humans, clinicians may be better able to identify persons who may be at increased risks for developing neuropathic pain during PAC therapy. PMID:26512050

  16. Blunted HPA Axis Activity in Suicide Attempters Compared to those at High Risk for Suicidal Behavior.

    PubMed

    Melhem, Nadine M; Keilp, John G; Porta, Giovanna; Oquendo, Maria A; Burke, Ainsley; Stanley, Barbara; Cooper, Thomas B; Mann, J John; Brent, David A

    2016-05-01

    Studies looking at the relationship of the hypothalamic-pituitary-adrenal (HPA) axis to suicidal behavior and its risk factors, such as depression, childhood abuse, and impulsive aggression, report inconsistent results. These studies also do not always differentiate between subjects who go on to attempt suicide, suicidal subjects who never attempted suicide, and non-suicidal subjects with psychiatric disorders. In this study, we examined cortisol responses to an experimental stressor, the Trier Social Stress Test (TSST), in 208 offspring of parents with mood disorder. Offspring suicide attempters showed lower total cortisol output (β=-0.47, 95% CI (-0.83, -0.11), p=0.01) compared with offspring with suicide-related behavior (SRB) but never attempted, non-suicidal offspring, and a healthy control group. The result remained significant even after controlling for sex, age, race, ethnicity, site, socio-economic status, and hour of the day when the TSST was conducted. Suicide attempters also showed lower baseline cortisol before the TSST (β=-0.45, 95% CI (-0.74, -0.17), p=0.002). However, there were no significant differences between the groups on cortisol reactivity to stress (β=4.5, 95% CI (-12.9, 22), p=0.61). Although subjects with suicide attempt and SRB have similar clinical and psychosocial characteristics, this is the first study to differentiate them biologically on HPA axis indices. Blunted HPA axis activity may increase risk for suicide attempt among individuals with psychopathology by reducing their ability to respond adaptively to ongoing stressors. These results may help better identify subjects at high risk for suicidal behavior for targeted prevention and intervention efforts.

  17. A Hyperresponsive HPA Axis May Confer Resilience Against Persistent Paclitaxel-Induced Mechanical Hypersensitivity.

    PubMed

    Kozachik, Sharon L; Page, Gayle G

    2016-05-01

    Paclitaxel (PAC) treatment is associated with persistent, debilitating neuropathic pain that affects the hands and feet. Female sex and biological stress responsivity are risk factors for persistent pain, but it is unclear whether these important biologically based factors confer risk for PAC-induced neuropathic pain. To determine the relative contributions of sex and hypothalamic-pituitary-adrenal (HPA)-axis stress responsivity to PAC-induced mechanical hypersensitivity, we employed a PAC protocol consisting of three, 2-week cycles of every-other-day doses of PAC 1 mg/kg versus saline (Week 1) and recovery (Week 2), totaling 42 days, in mature male and female Fischer 344, Lewis, and Sprague Dawley (SD) rats, known to differ in HPA axis stress responsivity. Mechanical sensitivity was operationalized using von Frey filaments, per the up-down method. Among PAC-injected rats, SD rats exhibited significantly greater mechanical hypersensitivity relative to accumulative PAC doses compared to Fischer 344 rats. Lewis rats were not significantly different in mechanical hypersensitivity from SD or Fischer 344 rats. At the end of the protocol, PAC-injected SD rats exhibited profound mechanical hypersensitivity, whereas the PAC-injected Fischer 344 rats appeared relatively resilient to the long-term effects of PAC and exhibited mechanical sensitivity that was not statistically different from their saline-injected counterparts. Sex differences were mixed and noted only early in the PAC protocol. Moderate HPA axis stress responsivity may confer additional risk for the painful effects of PAC. If these findings hold in humans, clinicians may be better able to identify persons who may be at increased risks for developing neuropathic pain during PAC therapy.

  18. Disrupting Hypothalamic Glucocorticoid Receptors Causes HPA Axis Hyperactivity and Excess Adiposity

    PubMed Central

    Laryea, Gloria; Schütz, Günther

    2013-01-01

    The glucocorticoid receptor (GR) regulates hypothalamic-pituitary-adrenal (HPA) axis activity during the stress response. The paraventricular nucleus (PVN) is a major site of negative feedback to coordinate the degree of the HPA axis activity with the magnitude of the exposed stressor. To define the function of endogenous PVN GR, we used Cre-loxP technology to disrupt different GR exons in Sim1-expressing neurons of the hypothalamus. GR exon 2-deleted mice (Sim1Cre-GRe2Δ) demonstrated 43% loss of PVN GR compared with an 87% GR loss in exon 3-deleted mice (Sim1Cre-GRe3Δ). Sim1Cre-GRe3Δ mice display stunted growth at birth but develop obesity in adulthood and display impaired stress-induced glucose release. We observed elevated basal and stress-induced corticosterone levels in Sim1Cre-GRe3Δ mice, compared with control and Sim1Cre-GRe2Δ mice, and impaired dexamethasone suppression, indicating an inability to negatively regulate corticosterone secretion. Sim1Cre-GRe3Δ mice also showed increased CRH mRNA in the PVN, increased basal plasma ACTH levels, and reduced locomotor behavior. We observed no differences in Sim1Cre-GRe2Δ mice compared with control mice in any measure. Our behavioral data suggest that GR deletion in Sim1-expressing neurons has no effect on anxiety or despair-like behavior under basal conditions. We conclude that loss of PVN GR results in severe HPA axis hyperactivity and Cushing's syndrome-like phenotype but does not affect anxiety and despair-like behaviors. PMID:23979842

  19. Hypothalamic-Pituitary-Adrenal Axis Programming after Recurrent Hypoglycemia during Development.

    PubMed

    Rao, Raghavendra

    2015-08-28

    Permanent brain injury is a complication of recurrent hypoglycemia during development. Recurrent hypoglycemia also has adverse consequences on the neuroendocrine system. Hypoglycemia-associated autonomic failure, characterized by ineffective glucose counterregulation during hypoglycemia, is well described in children and adults on insulin therapy for diabetes mellitus. Whether recurrent hypoglycemia also has a programming effect on the hypothalamus-pituitary-adrenal cortex (HPA) axis has not been well studied. Hypoglycemia is a potent stress that leads to increased glucocorticoid secretion in all age groups, including the perinatal period. Other conditions associated with exposure to excess glucocorticoid in the perinatal period have a programming effect on the HPA axis activity. Limited animal data suggest the possibility of similar programming effect after recurrent hypoglycemia in the postnatal period. The age at exposure to hypoglycemia likely determines the HPA axis response in adulthood. Recurrent hypoglycemia in the early postnatal period likely leads to a hyperresponsive HPA axis, whereas recurrent hypoglycemia in the late postnatal period lead to a hyporesponsive HPA axis in adulthood. The age-specific programming effects may determine the neuroendocrine response during hypoglycemia and other stressful events in individuals with history of recurrent hypoglycemia during development.

  20. Enhancing offspring hypothalamic-pituitary-adrenal (HPA) regulation via systematic novelty exposure: the influence of maternal HPA function

    PubMed Central

    Dinces, Sarah M.; Romeo, Russell D.; McEwen, Bruce S.; Tang, Akaysha C.

    2014-01-01

    In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother’s ability to mount a rapid corticosterone (CORT) response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring hypothalamic-pituitary-adrenal (HPA) regulation. Using a 2 × 2 within-litter design, one half of each litter were exposed to a relatively novel non-home environment for 3-min (Neo_Novel) daily during infancy (PND 1–21) and the other half of the litter remained in the home cage (Neo_Home); we further exposed half of these two groups to early adulthood (PND 54–63) novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting CORT (CORTB) and the ability to mount a large rapid CORT response (CORTE) to the onset of an acute stressor. Assessment of adult offspring’s ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring’s ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent

  1. Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

    PubMed

    Du, Xin; Pang, Terence Y

    2015-01-01

    There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer's, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies.

  2. Aging and the HPA axis: Stress and resilience in older adults.

    PubMed

    Gaffey, Allison E; Bergeman, C S; Clark, Lee Anna; Wirth, Michelle M

    2016-09-01

    Hypothalamic-pituitary-adrenal (HPA) axis function may change over the course of aging, and altered diurnal or stress-induced secretion of the hormone cortisol could predispose older adults to negative health outcomes. We propose that psychological resilience may interact with diurnal cortisol to affect health outcomes later in life. Emotion regulation and social support are two constructs that contribute to resilience and exhibit age-specific patterns in older adults. Determining how the use of resilience resources interacts with age-related diurnal cortisol will improve our understanding of the pathways between stress, resilience, and well-being. In this review, we assess published studies evaluating diurnal cortisol in older adults to better understand differences in their HPA axis functioning. Evidence thus far suggests that diurnal cortisol may increase with age, although cross-sectional studies limit the conclusions that can be drawn. We also review extant evidence connecting age-specific signatures of emotion regulation and social support with diurnal cortisol. Conclusions are used to propose a preliminary model demonstrating how resilience resources may modulate the effects of cortisol on health in aging.

  3. Differential menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls.

    PubMed

    Roca, Catherine A; Schmidt, Peter J; Altemus, Margaret; Deuster, Patricia; Danaceau, Merry A; Putnam, Karen; Rubinow, David R

    2003-07-01

    Previous studies in animals indicate that reproductive steroids are potent modulators of the hypothalamic-pituitary-adrenal (HPA) axis, a physiologic system that is typically dysregulated in affective disorders, such as major depression. Determination of the role of reproductive steroids in HPA axis regulation in humans is of importance when attempting to understand the pathophysiology of premenstrual syndrome (PMS), a disorder characterized by affective symptoms during the luteal phase of the menstrual cycle. We performed two studies using treadmill exercise stress testing to determine the effect of menstrual cycle phase and diagnosis on the HPA axis in women with PMS and controls and the role of gonadal steroids in HPA axis modulation in control women. The results of these studies indicate that women with PMS fail to show the normal increased HPA axis response to exercise during the luteal phase and that progesterone, not estradiol, produces increased HPA axis response to treadmill stress testing in control women. These data demonstrate that women with PMS, when symptomatic, appear to have an abnormal response to progesterone and, furthermore, do not display the HPA axis abnormalities characteristic of major depression.

  4. Social deprivation and the HPA axis in early development.

    PubMed

    Koss, Kalsea J; Hostinar, Camelia E; Donzella, Bonny; Gunnar, Megan R

    2014-12-01

    Growing evidence suggests that early social deprivation impacts the activity of the hypothalamic-pituitary-adrenocortical axis. Early adverse care in the form of institutional or orphanage care provides a human model for early social deprivation. The present study examined changes in diurnal cortisol during the transition to family care in the first 2 years post-adoption. Children adopted between 15 and 36 months from institutional care were examined four times during their first 2 years post-adoption (N=58). Comparison groups included same-aged peers reared in their birth families (N=50) and children adopted during their first year from overseas foster care (N=47). Children provided daily cortisol samples at roughly 2, 9, 17, and 25 months post-adoption. Post-institutionalized and post-foster care children exhibited less steep diurnal cortisol compared to non-adopted same-aged peers; these differences did not diminish across the 2 year period. For post-institutionalized children, lower social care quality in institutions was associated with less steep cortisol slopes. Lastly, shallower diurnal cortisol was a mediator between adoption status and increased behavioral problems 2 years post-adoption. Consistent with the non-human primate literature, early social deprivation may contribute to early programming of the HPA axis.

  5. HORSE SPECIES SYMPOSIUM: Glucocorticoid programming of hypothalamic-pituitary-adrenal axis and metabolic function: Animal studies from mouse to horse.

    PubMed

    Jellyman, J K; Valenzuela, O A; Fowden, A L

    2015-07-01

    Adrenal glucocorticoids, such as cortisol, are essential for normal fetal development and for maintaining homeostasis in adults. Developmental studies in humans and other animals have shown that exposure to excess glucocorticoids during critical windows of perinatal development can program permanent changes in hypothalamic-pituitary-adrenal (HPA) axis function and metabolic function, with adverse implications for the long-term health of the exposed offspring. The current review compares the programming of postnatal HPA axis function and glucose homeostasis among different species overexposed perinatally to glucocorticoids, with emphasis on the horse. The potential role of epigenetic modification of genes involved in the regulation of HPA axis and metabolic function at cellular and molecular levels is also discussed.

  6. HORSE SPECIES SYMPOSIUM: Glucocorticoid programming of hypothalamic-pituitary-adrenal axis and metabolic function: Animal studies from mouse to horse.

    PubMed

    Jellyman, J K; Valenzuela, O A; Fowden, A L

    2015-07-01

    Adrenal glucocorticoids, such as cortisol, are essential for normal fetal development and for maintaining homeostasis in adults. Developmental studies in humans and other animals have shown that exposure to excess glucocorticoids during critical windows of perinatal development can program permanent changes in hypothalamic-pituitary-adrenal (HPA) axis function and metabolic function, with adverse implications for the long-term health of the exposed offspring. The current review compares the programming of postnatal HPA axis function and glucose homeostasis among different species overexposed perinatally to glucocorticoids, with emphasis on the horse. The potential role of epigenetic modification of genes involved in the regulation of HPA axis and metabolic function at cellular and molecular levels is also discussed. PMID:26439993

  7. The Environmental Pollutant Tributyltin Chloride Disrupts the Hypothalamic-Pituitary-Adrenal Axis at Different Levels in Female Rats.

    PubMed

    Merlo, Eduardo; Podratz, Priscila L; Sena, Gabriela C; de Araújo, Julia F P; Lima, Leandro C F; Alves, Izabela S S; Gama-de-Souza, Letícia N; Pelição, Renan; Rodrigues, Lívia C M; Brandão, Poliane A A; Carneiro, Maria T W D; Pires, Rita G W; Martins-Silva, Cristina; Alarcon, Tamara A; Miranda-Alves, Leandro; Silva, Ian V; Graceli, Jones B

    2016-08-01

    Tributyltin chloride (TBT) is an environmental contaminant that is used as a biocide in antifouling paints. TBT has been shown to induce endocrine-disrupting effects. However, studies evaluating the effects of TBT on the hypothalamus-pituitary-adrenal (HPA) axis are especially rare. The current study demonstrates that exposure to TBT is critically responsible for the improper function of the mammalian HPA axis as well as the development of abnormal morphophysiology in the pituitary and adrenal glands. Female rats were treated with TBT, and their HPA axis morphophysiology was assessed. High CRH and low ACTH expression and high plasma corticosterone levels were detected in TBT rats. In addition, TBT leads to an increased in the inducible nitric oxide synthase protein expression in the hypothalamus of TBT rats. Morphophysiological abnormalities, including increases in inflammation, a disrupted cellular redox balance, apoptosis, and collagen deposition in the pituitary and adrenal glands, were observed in TBT rats. Increases in adiposity and peroxisome proliferator-activated receptor-γ protein expression in the adrenal gland were observed in TBT rats. Together, these data provide in vivo evidence that TBT leads to functional dissociation between CRH, ACTH, and costicosterone, which could be associated an inflammation and increased of inducible nitric oxide synthase expression in hypothalamus. Thus, TBT exerts toxic effects at different levels on the HPA axis function. PMID:27267847

  8. The Environmental Pollutant Tributyltin Chloride Disrupts the Hypothalamic-Pituitary-Adrenal Axis at Different Levels in Female Rats.

    PubMed

    Merlo, Eduardo; Podratz, Priscila L; Sena, Gabriela C; de Araújo, Julia F P; Lima, Leandro C F; Alves, Izabela S S; Gama-de-Souza, Letícia N; Pelição, Renan; Rodrigues, Lívia C M; Brandão, Poliane A A; Carneiro, Maria T W D; Pires, Rita G W; Martins-Silva, Cristina; Alarcon, Tamara A; Miranda-Alves, Leandro; Silva, Ian V; Graceli, Jones B

    2016-08-01

    Tributyltin chloride (TBT) is an environmental contaminant that is used as a biocide in antifouling paints. TBT has been shown to induce endocrine-disrupting effects. However, studies evaluating the effects of TBT on the hypothalamus-pituitary-adrenal (HPA) axis are especially rare. The current study demonstrates that exposure to TBT is critically responsible for the improper function of the mammalian HPA axis as well as the development of abnormal morphophysiology in the pituitary and adrenal glands. Female rats were treated with TBT, and their HPA axis morphophysiology was assessed. High CRH and low ACTH expression and high plasma corticosterone levels were detected in TBT rats. In addition, TBT leads to an increased in the inducible nitric oxide synthase protein expression in the hypothalamus of TBT rats. Morphophysiological abnormalities, including increases in inflammation, a disrupted cellular redox balance, apoptosis, and collagen deposition in the pituitary and adrenal glands, were observed in TBT rats. Increases in adiposity and peroxisome proliferator-activated receptor-γ protein expression in the adrenal gland were observed in TBT rats. Together, these data provide in vivo evidence that TBT leads to functional dissociation between CRH, ACTH, and costicosterone, which could be associated an inflammation and increased of inducible nitric oxide synthase expression in hypothalamus. Thus, TBT exerts toxic effects at different levels on the HPA axis function.

  9. Concurrent and prospective associations between HPA axis activity and depression symptoms in newlywed women

    PubMed Central

    Ge, Fiona; Pietromonaco, Paula R.; DeBuse, Casey J.; Powers, Sally I.; Granger, Douglas A.

    2016-01-01

    We investigated the extent to which individual differences in activity of the hypothalamic pituitary adrenal axis (HPA) are associated with depressive symptoms among newlywed couples. Participants were 218 couples (M age 28.4 years; 94% White) who provided 5 saliva samples (later assayed for cortisol and DHEA-S) before and after participation in a discussion of a major area of disagreement in their relationship. Depressive symptoms were assessed initially, and approximately 19- and 37-months later. Results revealed an interactive effect suggesting that concordant levels of cortisol and DHEA-S (either both high or both low) were concurrently and prospectively associated with higher depression scores. Interestingly, this interactive effect was observed for wives only – not for husbands. These observations underscore contemporary theoretical assumptions that the expression of the association between HPA activity and depression is dependent on factors related to the interaction between characteristics of the person and features of the social environment, and moderated by co-occurring variation in endocrine milieu. PMID:27494071

  10. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; Ramírez-Expósito, María Jesús

    2003-06-20

    Local renin-angiotensin systems (RAS) have been postulated in brain, pituitary and adrenal glands. These local RAS have been implicated, respectively, in the central regulation of the cardiovascular system and body water balance, the secretion of pituitary hormones and the secretion of aldosterone by adrenal glands. By other hand, it is known that the hypothalamus-pituitary-adrenal (HPA) axis is involved in blood pressure regulation, and is affected by sex hormones. The aim of the present work is to analyze the influence of testosterone on RAS-regulating aminopeptidase A, B and M activities and vasopressin-degrading activity in the HPA axis, measuring these activities in their soluble and membrane-bound forms in the hypothalamus, pituitary and adrenal glands of orchidectomized males and orchidectomized males treated subcutaneously with several doses of testosterone. The present data suggest that in male mice, testosterone influences the RAS- and vasopressin-degrading activities at all levels of the HPA axis.

  11. The critical importance of the fetal hypothalamus-pituitary-adrenal axis

    PubMed Central

    Wood, Charles E.; Keller-Wood, Maureen

    2016-01-01

    The fetal hypothalamus-pituitary-adrenal (HPA) axis is at the center of mechanisms controlling fetal readiness for birth, survival after birth and, in several species, determination of the timing of birth. Stereotypical increases in fetal HPA axis activity at the end of gestation are critical for preparing the fetus for successful transition to postnatal life. The fundamental importance in fetal development of the endogenous activation of this endocrine axis at the end of gestation has led to the use of glucocorticoids for reducing neonatal morbidity in premature infants. However, the choice of dose and repetition of treatments has been controversial, raising the possibility that excess glucocorticoid might program an increased incidence of adult disease (e.g., coronary artery disease and diabetes). We make the argument that because of the critical importance of the fetal HPA axis and its interaction with the maternal HPA axis, dysregulation of cortisol plasma concentrations or inappropriate manipulation pharmacologically can have negative consequences at the beginning of extrauterine life and for decades thereafter. PMID:26918188

  12. Relationship between hypothalamic-pituitary-adrenal axis responsiveness and age, sexual maturity status, and sex in Japanese quail selected for long or short duration of tonic immobility.

    PubMed

    Hazard, D; Couty, M; Faure, J M; Guémené, D

    2005-12-01

    The influences of age (4 to 12 wk), sexual maturity status, and sex on hypothalamic-pituitary-adrenal (HPA) axis responsiveness were investigated by measuring changes in peripheral basal levels of corticosterone (B) and responses to 10 min of physical restraint in a crush cage or injection of 1-24 adrenocorticotropic hormone (ACTH) in 2 genotypes of Japanese quail divergently selected for long (LTI) or short (STI) duration of tonic immobility (TI). Although gonad development was more advanced in male STI quail, most birds were still immature at 4 wk of age, but sexual maturity was fully acquired by 6 wk of age in both sexes and genotypes. This change was associated with increases in basal B levels in both genotypes and sexes. On the other hand, HPA axis responsiveness to restraint and adrenal responsiveness to 1-24 ACTH injection remained stable in STI quail, whatever the age. Conversely, significant responses to restraint compared with basal B levels were only observed at 4 and 6 wk of age, and adrenal responsiveness increased with age in LTI quail. Moreover, higher B levels were measured in response to restraint in STI than in LTI quail, whereas similar adrenal responses were measured at 9 and 12 wk of age. We concluded that an increase in basal B levels is associated with the stage of sexual maturity acquired, but it did not affect HPA axis responsiveness or adrenal B response capacity. On the other hand, age affected HPA axis responsiveness and adrenal B response capacity in LTI quail of both sexes but not in STI quail. It is hypothesized that functional HPA axis maturity occurs after 6 wk of age in the LTI genotype, but it is reached by 4 wk of age in the STI genotype. In conclusion, the divergent selection program for TI conducted on quail resulted in changes in HPA responsiveness that probably resulted from differences in development rate and function of the adrenal glands or other upstream structures of the HPA axis.

  13. Stress Responsiveness of the Hypothalamic–Pituitary–Adrenal Axis: Age-Related Features of the Vasopressinergic Regulation

    PubMed Central

    Goncharova, Nadezhda D.

    2013-01-01

    The hypothalamic–pituitary–adrenal (HPA) axis plays a key role in adaptation to environmental stresses. Parvicellular neurons of the hypothalamic paraventricular nucleus secrete corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) into pituitary portal system; CRH and AVP stimulate adrenocorticotropic hormone (ACTH) release through specific G-protein-coupled membrane receptors on pituitary corticotrophs, CRHR1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response to ACTH. The glucocorticoids activate specific receptors in brain and peripheral tissues thereby triggering the necessary metabolic, immune, neuromodulatory, and behavioral changes to resist stress. While importance of CRH, as a key hypothalamic factor of HPA axis regulation in basal and stress conditions in most species, is generally recognized, role of AVP remains to be clarified. This review focuses on the role of AVP in the regulation of stress responsiveness of the HPA axis with emphasis on the effects of aging on vasopressinergic regulation of HPA axis stress responsiveness. Under most of the known stressors, AVP is necessary for acute ACTH secretion but in a context-specific manner. The current data on the AVP role in regulation of HPA responsiveness to chronic stress in adulthood are rather contradictory. The importance of the vasopressinergic regulation of the HPA stress responsiveness is greatest during fetal development, in neonatal period, and in the lactating adult. Aging associated with increased variability in several parameters of HPA function including basal state, responsiveness to stressors, and special testing. Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory and requires further research. Many contradictory results may be due to age and species differences in the HPA function of rodents and primates. PMID:23486926

  14. Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro.

    PubMed

    Gisslinger, H; Svoboda, T; Clodi, M; Gilly, B; Ludwig, H; Havelec, L; Luger, A

    1993-03-01

    The successful therapeutic use of interferon-alpha (IFN-alpha) in myeloproliferative disorders offered the possibility to test its acute and long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis in humans. ACTH and cortisol plasma concentrations were measured in 8 patients hourly starting from 4 p.m. through 12 p.m. on three occasions. The first time all patients were studied before initiation of therapy, when the vehicle was injected alone. The patients were studied again on day 1 of IFN-alpha therapy (5 million units) and once more after 3 weeks of therapy. On the control day, plasma concentrations of ACTH and cortisol were in the range expected for this time of day. In contrast, after the first administration of IFN-alpha a significant stimulation of the HPA axis was observed. After 3 weeks of IFN-alpha therapy, no significant stimulation of the HPA axis occurred after administration of IFN-alpha. IFN-alpha-induced adaptive changes in the HPA axis were also indicated by a significantly enhanced ACTH and cortisol response to exogenously administered supramaximal doses of corticotropin-releasing hormone (CRH) when the patients had been on IFN-alpha treatment for 3 weeks. To determine the exact locus of the IFN-alpha action, in vitro experiments were performed using rat hypothalamic organ and primary pituitary and adrenal cell culture systems. Thereby a significant stimulation of hypothalamic CRH secretion and rat adrenal corticosterone production was observed after INF-alpha at concentrations of 5 x 10(-8) M or 10(-7) M respectively. In contrast, no direct IFN-alpha effect on pituitary ACTH secretion could be observed in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. The Defecation Index as a Measure of Emotionality: Questions Raised by HPA Axis and Prolactin Response to Stress in the Maudsley Model.

    PubMed

    Blizard, David A; Eldridge, J Charles; Jones, Byron C

    2015-05-01

    The Maudsley Reactive and Maudsley Non-Reactive strains have been selectively bred for differences in open-field defecation (OFD), a putative index of stress. We investigated whether variations in the hypothalamic-pituitary-adrenal (HPA) axis are correlated with strain differences in OFD in the Maudsley model. Exposure to the open-field test did not result in increases in ACTH in male rats of either strain and there were no strain differences in the large increases in ACTH and corticosteroid that occurred in response to intermittent footshock. Parallel studies of prolactin showed that Maudsley Reactive rats had greater response to the open-field and to footshock than Maudsley Non-Reactive rats. The lack of correlation between strain differences in OFD and reactivity of the HPA axis is consistent with the idea that HPA response to stress and OFD reflect the output of different neural systems and that individual differences in emotionality, as indexed by OFD do not influence other measures of stress-reactivity in a simple manner, if at all. The reactivity of the prolactin system to the open-field test and lack of response of ACTH to the same situation is consistent with the idea that the prolactin system is sensitive to lower levels of stress than the HPA axis, a finding at variance with the presumed extreme sensitivity of the latter system. Earlier comparisons of the HPA axis in these strains implicate local factors such as neuropeptide-Y peptide in the adrenal in attenuating the response of the adrenal cortex to ACTH and hints at the complexity of regulation of the HPA axis.

  16. The Defecation Index as a Measure of Emotionality: Questions Raised by HPA Axis and Prolactin Response to Stress in the Maudsley Model.

    PubMed

    Blizard, David A; Eldridge, J Charles; Jones, Byron C

    2015-05-01

    The Maudsley Reactive and Maudsley Non-Reactive strains have been selectively bred for differences in open-field defecation (OFD), a putative index of stress. We investigated whether variations in the hypothalamic-pituitary-adrenal (HPA) axis are correlated with strain differences in OFD in the Maudsley model. Exposure to the open-field test did not result in increases in ACTH in male rats of either strain and there were no strain differences in the large increases in ACTH and corticosteroid that occurred in response to intermittent footshock. Parallel studies of prolactin showed that Maudsley Reactive rats had greater response to the open-field and to footshock than Maudsley Non-Reactive rats. The lack of correlation between strain differences in OFD and reactivity of the HPA axis is consistent with the idea that HPA response to stress and OFD reflect the output of different neural systems and that individual differences in emotionality, as indexed by OFD do not influence other measures of stress-reactivity in a simple manner, if at all. The reactivity of the prolactin system to the open-field test and lack of response of ACTH to the same situation is consistent with the idea that the prolactin system is sensitive to lower levels of stress than the HPA axis, a finding at variance with the presumed extreme sensitivity of the latter system. Earlier comparisons of the HPA axis in these strains implicate local factors such as neuropeptide-Y peptide in the adrenal in attenuating the response of the adrenal cortex to ACTH and hints at the complexity of regulation of the HPA axis. PMID:25911177

  17. Glutamatergic and HPA-axis pathway genes in bipolar disorder comorbid with alcohol- and substance use disorders.

    PubMed

    Dalvie, Shareefa; Fabbri, Chiara; Ramesar, Raj; Serretti, Alessandro; Stein, Dan J

    2016-02-01

    Glutamatergic neurotransmission has been shown to be dysregulated in bipolar disorder (BD), alcohol use disorder (AUD) and substance use disorder (SUD). Similarly, disruption in the hypothalamic-pituitary-adrenal (HPA)-axis has also been observed in these conditions. BD is often comorbid with AUD and SUD. The effects of the glutamatergic and HPA systems have not been extensively examined in individuals with BD-AUD and BD-SUD comorbidity. The aim of this investigation was to determine whether variants in the glutamatergic pathway and HPA-axis are associated with BD-AUD and BD-SUD comorbidity. The research cohort consisted of 498 individuals with BD type I from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). A subset of the cohort had comorbid current AUD and current SUD. A total of 1935 SNPs from both the glutamatergic and HPA pathways were selected from the STEP-BD genome-wide dataset. To identify population stratification, IBS clustering was performed using the program Plink 1.07. Single SNP association and gene-based association testing were conducted using logistic regression. A pathway analysis of glutamatergic and HPA genes was performed, after imputation using IMPUTE2. No single SNP was associated with BD-AUD or BD-SUD comorbidity after correction for multiple testing. However, from the gene-based analysis, the gene PRKCI was significantly associated with BD-AUD. The pathway analysis provided overall negative findings, although several genes including GRIN2B showed high percentage of associated SNPs for BD-AUD. Even though the glutamatergic and HPA pathways may not be involved in BD-AUD and BD-SUD comorbidity, PRKCI deserves further investigation in BD-AUD.

  18. Hypothalamus-Pituitary-Adrenal Axis Hypersuppression Is Associated with Gastrointestinal Symptoms in Major Depression

    PubMed Central

    Karling, Pontus; Wikgren, Mikael; Adolfsson, Rolf; Norrback, Karl-Fredrik

    2016-01-01

    Background/Aims Gastrointestinal symptoms and hypothalamus-pituitary-adrenal (HPA) axis dysfunction are frequently observed in patients with major depression. The primary aim of the study was to investigate the relationship between HPA-axis function and self-perceived functional gastrointestinal symptoms in major depression. Methods Patients with major depression (n = 73) and controls representative of the general population (n = 146) underwent a weight-adjusted very low dose dexamethasone suppression test (DST). Patients and controls completed the gastrointestinal symptom rating scale-iritable bowel syndrome (GSRS-IBS) and the hospital anxiety depression scale. Medical records of the patients were screened over a ten year period for functional gastrointestinal disorder and pain conditions. Results Patients with high GSRS-IBS scores (above median) exhibited HPA-axis hypersuppression more often than controls (defined by the lowest 10% cutoff of the post-DST cortisol values among controls, adjusted OR 7.25, CI 1.97–26.7) whereas patients with low GSRS-IBS scores did not differ from controls concerning their post-DST cortisol values. Patients who had consulted primary care for functional gastrointestinal disorder (P = 0.039), lumbago (P = 0.006) and chronic multifocal pain (P = 0.057) also exhibited an increased frequency of hypersuppression. Conclusions HPA-axis hypersuppression is associated with functional gastrointestinal symptoms in patients with major depression. PMID:26507800

  19. Regulation of the Hypothalamic-Pituitary-Adrenal Axis Circadian Rhythm by Endocannabinoids Is Sexually Diergic

    PubMed Central

    Atkinson, Helen C.; Leggett, James D.; Wood, Susan A.; Castrique, Emma S.; Kershaw, Yvonne M.; Lightman, Stafford L.

    2010-01-01

    We have examined the effects of acute administration of the cannabinoid receptor type 1 (CB1) antagonist AM251 on the rat hypothalamic-pituitary-adrenal (HPA) axis with respect to both gender and time of day. Blood samples were collected from conscious male and female rats every 5 min using an automated blood sampling system, and corticosterone concentrations were determined. In male rats, there was a distinct diurnal effect of AM251 with a greater activation of the HPA axis in the morning (diurnal trough) compared with the evening (diurnal peak). At both times of the day, circulating corticosterone concentrations were elevated for approximately 4 h after AM251 administration. In female rats, there was also diurnal variation in the activation of the HPA axis; however, these effects were not as profound as those in males. Corticosterone concentrations were only slightly elevated at the diurnal trough and for a shorter time period than in males (2 compared with 4 h). Moreover, there was no effect of AM251 on corticosterone concentrations when administered at the diurnal peak. Subsequent studies, only in males, in which both ACTH and corticosterone were measured, confirmed that the effects of AM251 on corticosterone were mediated by ACTH. Moreover, the elevation of both ACTH and corticosterone could be replicated using another CB1 antagonist, AM281. These data demonstrate that the extent and duration of HPA axis activation after CB1 blockade are clearly dependent on both gender and time of day. PMID:20534730

  20. Modulatory activity of soluble beta amyloid on HPA axis function in rats.

    PubMed

    Morgese, Maria Grazia; Tucci, Paolo; Colaianna, Marilena; Zotti, Margherita; Cuomo, Vincenzo; Schiavone, Stefania; Trabace, Luigia

    2014-01-01

    Despite the consolidation of the amyloid hypothesis, the main component of senile plaques in Alzheimer's disease (AD), recent findings have led to a conceptual shift opening new questions about the potential physiological role of this peptide. In addition, soluble beta amyloid (sBA), in transgenic AD model, resulted to be increased after chronic and acute stress and alterations in cortisol levels have been reported in AD. Impaired hypothalamic pituitary adrenal (HPA) axis has been linked to depressive state and, consistently, we have previously demonstrated that BA is able to provoke depressive-like profile in rats. Here we further analysed the effect of the peptide in behavioural paradigms used to study emotional and cognitive response, by using the passive avoidance task, for cognitive parameters, and the sucrose preference test (SPT), to evaluate anhedonia. Moreover, in order to correlate behavioural with neurochemical and neuroendocrinal data, we investigated the effects of the peptide on noradrenergic system in amygdala (AMY), prefrontal cortex (PFC) and hippocampus (HIPP) along with plasmatic corticosterone and hypothalamic corticotrophin releasing factor (CRF). We found that BA-treated animals showed an impaired memory consolidation of inhibitory avoidance training, while no effect was evident in SPT. These results lead us to hypothesize a different response to stress coping behaviour in BA treated rats. Moreover, BA caused a significant increase in noradrenaline (NA) in PFC and HIPP, while in AMY was decreased. Consistently, we found a significant decrease in plasma corticosterone concentrations in BA-treated rats. Taken together, our data suggest that BA exerts an inhibitory effect on HPA axis activation.

  1. Behavioral sexual dimorphism in models of anxiety and depression due to changes in HPA axis activity.

    PubMed

    Kokras, Nikolaos; Dalla, Christina; Sideris, Antonios C; Dendi, Artemis; Mikail, Hudu G; Antoniou, Katerina; Papadopoulou-Daifoti, Zeta

    2012-01-01

    Anxiety and depression are considered as stress-related disorders, which present considerable sex differentiation. In animal models of anxiety and depression sex differences have been described and linked to the sexually dimorphic hypothalamus-pituitary-adrenals (HPA) axis. The present study aimed to adjust corticosterone, the main HPA axis stress hormone, in male and female adrenalectomized rats with oral (25 μg/ml) corticosterone replacement (ADXR). Subsequently we investigated the behavioral performance of ADXR rats in the open field, light/dark and forced swim test (FST). Male ADXR rats showed less anxiety-like behavior when compared to sham-operated controls, despite adequate corticosterone replacement. They further showed increased swimming and reduced climbing behavior in the FST, while immobility duration did not differ from sham-operated males. On the contrary, adrenalectomy and corticosterone replacement did not have significant effects on the female behavioral response. Females were generally more active and presented less anxiety-like behavior than males, while they exhibited higher depressive-like symptomatology in the FST. ADXR affected behavioral responses predominantly in males, which in turn modified sex differences in the behavioral profile. Females in proestrous and estrous did not differ from females in diestrous and methestrous in any measured behavioral response. Present results suggest that the male and not the female behavioral responses in models of anxiety and depression were mainly affected by ADXR. These findings may play a significant role in explaining the differential coping strategy of the two sexes in response to stressful experiences. This article is part of a Special Issue entitled 'Anxiety and Depression'.

  2. Trauma exposure and hypothalamic-pituitary- adrenal axis functioning in mentally healthy Dutch peacekeeping veterans, 10-25 years after deployment.

    PubMed

    Klaassens, Ellen R; van Veen, Tineke; Giltay, Erik J; Rinne, Thomas; van Pelt, Johannes; Zitman, Frans G

    2010-02-01

    Hypothalamic-pituitary-adrenal (HPA) axis alterations have been found in veterans with posttraumatic stress disorder (PTSD). It is unclear whether trauma exposure during adulthood in the absence of psychopathology is also associated with HPA-axis dysregulation. Thirty-six trauma-exposed peacekeepers, 23 nonexposed peacekeepers, and 25 nonexposed civilians, all without lifetime psychopathology were studied. Basal HPA-axis functioning was assessed with salivary cortisol samples obtained over 2 days. HPA-axis reactivity was assessed with the dexamethasone/corticotropin-releasing hormone test. Lower afternoon salivary cortisol levels were found in both veteran groups versus controls after adjustment for confounders. The authors concluded that this study does not support the idea that HPA-axis functioning is durably altered by trauma exposure during adulthood in men. PMID:20146391

  3. Adult consequences of post-weaning high fat feeding on the limbic-HPA axis of female rats.

    PubMed

    Boukouvalas, George; Gerozissis, Kyriaki; Kitraki, Efthimia

    2010-05-01

    The peripubertal period is critical for the final maturation of circuits controlling energy homeostasis and stress response. However, the consequence of juvenile fat consumption on adult physiology is not clear. This study analyzed the adult consequences of post-weaning fat feeding on limbic-hypothalamic-pituitary-adrenal (HPA) axis components and on metabolic regulators of female rats. Wistar rats were fed either a high fat (HF) diet or the normal chow from weaning to puberty or to 3 months of age. Additional groups crossed their diets at puberty onset. Plasma leptin, insulin, and corticosterone levels were determined by radioimmunoassay and their brain receptors by western blot analysis. Adult HF-fed animals though not overweight, had higher corticosterone and reduced glucocorticoid receptor levels in the hypothalamus and hippocampus, compared to the controls. The alterations in HPA axis emerged already at puberty onset. Leptin receptor levels in the hypothalamus were reduced only by continuous fat feeding from weaning to adulthood. The pre-pubertal period appeared more vulnerable to diet-induced alterations in adulthood than the post-pubertal one. Switching from fat diet to normal chow at puberty onset restored most of the diet-induced alterations in the HPA axis. The corticosteroid circuit rather than the leptin or insulin system appears as the principal target for the peripubertal fat diet-induced effects in adult female rats.

  4. The Effect of Nicotine on HPA Axis Activity in Females is Modulated by the FKBP5 Genotype.

    PubMed

    Koopmann, Anne; Bez, Jennifer; Lemenager, Tagrid; Hermann, Derik; Dinter, Christina; Reinhard, Iris; Schuster, Rilana; Wiedemann, Klaus; Winterer, Georg; Kiefer, Falk

    2016-05-01

    Tobacco smoking modulates activity in the hypothalamic-pituitary-adrenal (HPA) axis and is used to cope with stress, especially by females. The single nucleotide polymorphism (SNP) rs1360780, linked to FK506-binding protein 51 (FKBP5), has been shown to affect HPA axis functioning, and has thus been suggested as a promising candidate for indicating vulnerability to stress-related disorders. The aim of this study was to investigate the interaction between nicotine consumption and rs1360780 on cortisol plasma levels in females. A total of 296 female smokers (assessed by the Fagerström Test for Nicotine Dependence; FTND) were genotyped for the SNP rs1360780. We measured participants' cortisol plasma concentration in blood plasma collected 3 h after standardized tobacco smoking exposure. In the 36 TT-homozygotes, we found a significant negative correlation between the FTND sum score and cortisol plasma concentrations. Using linear regression analysis, we found that the FTND sum score accounted for 12.4% of the variance of cortisol plasma levels. This association was not detected in C-allele carriers. Our results suggest that nicotine is an important confounder in the modulation of HPA axis activity by FKBP5. In light of these findings, future studies on FKBP5 should seek to include data on nicotine consumption as a covariate.

  5. Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes.

    PubMed

    Mavroudis, Panteleimon D; Corbett, Siobhan A; Calvano, Steven E; Androulakis, Ioannis P

    2014-10-15

    In this work we propose a semimechanistic model that describes the photic signal transduction to the hypothalamic-pituitary-adrenal (HPA) axis that ultimately regulates the synchronization of peripheral clock genes (PCGs). Our HPA axis model predicts that photic stimulation induces a type-1 phase response curve to cortisol's profile with increased cortisol sensitivity to light exposure in its rising phase, as well as the shortening of cortisol's period as constant light increases (Aschoff's first rule). Furthermore, our model provides insight into cortisol's phase and amplitude dependence on photoperiods and reveals that cortisol maintains highest amplitude variability when it is entrained by a balanced schedule of light and dark periods. Importantly, by incorporating the links between HPA axis and PCGs we were able to investigate how cortisol secretion impacts the entrainment of a population of peripheral cells and show that disrupted light schedules, leading to blunted cortisol secretion, fail to synchronize a population of PCGs which further signifies the loss of circadian rhythmicity in the periphery of the body.

  6. Association, haplotype, and gene-gene interactions of the HPA axis genes with suicidal behaviour in affective disorders.

    PubMed

    Leszczyńska-Rodziewicz, Anna; Szczepankiewicz, Aleksandra; Pawlak, Joanna; Dmitrzak-Weglarz, Monika; Hauser, Joanna

    2013-01-01

    Family twin and adoption studies have noted the heritability of specific biological factors that influence suicidal behaviour. Exposure to stress is one of the factors that strongly contribute to suicide attempts. The biological response to stress involves the hypothalamic-pituitary-adrenal axis (HPA). Therefore, we found it interesting to study polymorphisms of genes involved in the HPA axis (CRHR1, NR3C1, and AVPBR1). The study was performed on 597 patients, 225 of whom had a history of suicide attempts. We did not observe any significant differences in the studied polymorphisms between the group of patients with a history of suicide attempts and the control subjects. Our haplotype analysis of the AVPR1b gene revealed an association between the GCA haplotype and suicide attempts; however, this association was not significant after correcting for multiple testing. We did not observe any other association in haplotype and MDR analysis. We report here a comprehensive analysis of the HPA axis genes and a lack of association for genetic variations regarding the risk of suicide attempts in affective disorder patients. Nonetheless, the inconsistencies with the previously published results indicate the importance of the further investigation of these polymorphisms with respect to the risk of suicide attempts.

  7. Stress-induced sensitization: the hypothalamic-pituitary-adrenal axis and beyond.

    PubMed

    Belda, Xavier; Fuentes, Silvia; Daviu, Nuria; Nadal, Roser; Armario, Antonio

    2015-01-01

    Exposure to certain acute and chronic stressors results in an immediate behavioral and physiological response to the situation followed by a period of days when cross-sensitization to further novel stressors is observed. Cross-sensitization affects to different behavioral and physiological systems, more particularly to the hypothalamus-pituitary-adrenal (HPA) axis. It appears that the nature of the initial (triggering) stressor plays a major role, HPA cross-sensitization being more widely observed with systemic or high-intensity emotional stressors. Less important appears to be the nature of the novel (challenging) stressor, although HPA cross-sensitization is better observed with short duration (5-15 min) challenging stressors. In some studies with acute immune stressors, HPA sensitization appears to develop over time (incubation), but most results indicate a strong initial sensitization that progressively declines over the days. Sensitization can affect other physiological system (i.e. plasma catecholamines, brain monoamines), but it is not a general phenomenon. When studied concurrently, behavioral sensitization appears to persist longer than that of the HPA axis, a finding of interest regarding long-term consequences of traumatic stress. In many cases, behavioral and physiological consequences of prior stress can only be observed following imposition of a new stressor, suggesting long-term latent effects of the initial exposure.

  8. The stability of the extended model of hypothalamic-pituitary-adrenal axis examined by stoichiometric network analysis

    NASA Astrophysics Data System (ADS)

    Marković, V. M.; Čupić, Ž.; Ivanović, A.; Kolar-Anić, Lj.

    2011-12-01

    Stoichiometric network analysis (SNA) represents a powerful mathematical tool for stability analysis of complex stoichiometric networks. Recently, the important improvement of the method has been made, according to which instability relations can be entirely expressed via reaction rates, instead of thus far used, in general case undefined, current rates. Such an improved SNA methodology was applied to the determination of exact instability conditions of the extended model of the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrinological system, whose hormone concentrations exert complex oscillatory evolution. For emergence of oscillations, the Hopf bifurcation condition was utilized. Instability relations predicted by SNA showed good correlation with numerical simulation data of the HPA axis model.

  9. Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones.

    PubMed

    Stephens, Mary Ann C; Mahon, Pamela B; McCaul, Mary E; Wand, Gary S

    2016-04-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the

  10. Neuroendocrine Regulation of Anxiety: Beyond the Hypothalamic-Pituitary-Adrenal Axis.

    PubMed

    Borrow, A P; Stranahan, A M; Suchecki, D; Yunes, R

    2016-07-01

    The central nervous system regulates and responds to endocrine signals, and this reciprocal relationship determines emotional processing and behavioural anxiety. Although the hypothalamic-pituitary-adrenal (HPA) axis remains the best-characterised system for this relationship, other steroid and peptide hormones are increasingly recognised for their effects on anxiety-like behaviour and reward. The present review examines recent developments related to the role of a number of different hormones in anxiety, including pregnane neurosteroids, gut peptides, neuropeptides and hormonal signals derived from fatty acids. Findings from both basic and clinical studies suggest that these alternative systems may complement or occlude stress-induced changes in anxiety and anxiety-like behaviour. By broadening the scope of mechanisms for depression and anxiety, it may be possible to develop novel strategies to attenuate stress-related psychiatric conditions. The targets for these potential therapies, as discussed in this review, encompass multiple circuits and systems, including those outside of the HPA axis. PMID:27318180

  11. Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

    PubMed Central

    Du, Xin; Pang, Terence Y.

    2015-01-01

    There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic–pituitary–adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer’s, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies. PMID:25806005

  12. Effects of orchidectomy and testosterone replacement on mouse enkephalin-degrading aminopeptidase activity in the HPA axis.

    PubMed

    García-López, M J; Martínez-Martos, J M; Mayas, M D; Carrera, M P; Ramírez-Expósito, M J

    2003-12-01

    Opiates are involved in the regulation of several functions in the hypothalamus-pituitary-adrenal (HPA) axis under physiological conditions. The aim of the present work is to study the influence of orchidectomy and testosterone (T) replacement on soluble (S) and membrane bound (MB) enkephalin-degrading aminopeptidase (EDA) activities in the HPA axis. Forty male mice (Balb/C) were distributed in five groups: sham-operated control (C), orchidectomized (OR-C), and orchidectomized treated with increasing doses of T (3, 6 or 12 mg/kg). In hypothalamus, orchidectomy did not modify either S or MB EDA, although T replacement increased S but not MB EDA. In pituitary, neither S nor MB EDA activities changed with orchidectomy, although both activities changed after T replacement. On the other hand, in adrenal glands, orchidectomy increased S and MB EDA activities, whereas T replacement returned both activities to control levels. These results suggest a direct effect of T in S and MB EDA activities and therefore, an influence on their endogenous substrates regulation.

  13. Vitamin A regulates hypothalamic-pituitary-adrenal axis status in LOU/C rats.

    PubMed

    Marissal-Arvy, Nathalie; Hamiani, Rachel; Richard, Emmanuel; Moisan, Marie-Pierre; Pallet, Véronique

    2013-10-01

    The aim of this study was to explore the involvement of retinoids in the hypoactivity and hyporeactivity to stress of the hypothalamic-pituitary-adrenal (HPA) axis in LOU/C rats. We measured the effects of vitamin A deficiency administered or not with retinoic acid (RA) on plasma corticosterone in standard conditions and in response to restraint stress and on hypothalamic and hippocampal expression of corticosteroid receptors, corticotropin-releasing hormone and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in LOU/C rats. Interestingly, under control conditions, we measured a higher plasma concentration of retinol in LOU/C than in Wistar rats, which could contribute to the lower basal activity of the HPA axis in LOU/C rats. Vitamin A deficiency induced an increased HPA axis activity in LOU/C rats, normalized by RA administration. Compared with LOU/C control rats, vitamin A-deficient rats showed a delayed and heightened corticosterone response to restraint stress. The expression of corticosteroid receptors was strongly decreased by vitamin A deficiency in the hippocampus, which could contribute to a less efficient feedback by corticosterone on HPA axis tone. The expression of 11β-HSD1 was increased by vitamin A deficiency in the hypothalamus (+62.5%) as in the hippocampus (+104.7%), which could lead to a higher production of corticosterone locally and contribute to alteration of the hippocampus. RA supplementation treatment restored corticosterone concentrations and 11β-HSD1 expression to control levels. The high vitamin A status of LOU/C rats could contribute to their low HPA axis activity/reactivity and to a protective effect against 11β-HSD1-mediated deleterious action on cognitive performances during ageing. PMID:23847298

  14. The effect of sex and irritable bowel syndrome on HPA axis response and peripheral glucocorticoid receptor expression

    PubMed Central

    Videlock, Elizabeth J.; Shih, Wendy; Adeyemo, Mopelola; Mahurkar-Joshi, Swapna; Presson, Angela P.; Polytarchou, Christos; Alberto, Melissa; Iliopoulos, Dimitrios; Mayer, Emeran A.; Chang, Lin

    2016-01-01

    Background and aims Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been reported in irritable bowel syndrome (IBS). Enhanced HPA axis response has been associated with reduced glucocorticoid receptor (GR) mediated negative feedback inhibition. We aimed to study the effects of IBS status, sex, or presence of early adverse life events (EAL) on the cortisol response to corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH), and on GR mRNA expression in peripheral blood mononuclear cells (PBMCs). Methods Rome III+ IBS patients and healthy controls underwent CRF (1 μg/kg ovine) and ACTH (250 μg) stimulation tests with serial plasma ACTH and cortisol levels measured (n = 116). GR mRNA levels were measured using quantitative PCR (n = 143). Area under the curve (AUC) and linear mixed effects models were used to compare ACTH and cortisol response measured across time between groups. Results There were divergent effects of IBS on the cortisol response to ACTH by sex. In men, IBS was associated with an increased AUC (p = 0.009), but in women AUC was blunted in IBS (p = 0.006). Men also had reduced GR mRNA expression (p = 0.007). Cumulative exposure to EALs was associated with an increased HPA response. Lower GR mRNA was associated with increased pituitary HPA response and increased severity of overall symptoms and abdominal pain in IBS. Conclusion This study highlights the importance of considering sex in studies of IBS and the stress response in general. Our findings also provide support for PBMC GR mRNA expression as a peripheral marker of central HPA response. PMID:27038676

  15. Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis.

    PubMed

    Diz-Chaves, Yolanda; Gil-Lozano, Manuel; Toba, Laura; Fandiño, Juan; Ogando, Hugo; González-Matías, Lucas C; Mallo, Federico

    2016-08-01

    Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

  16. Association of HPA axis-related genetic variation with stress reactivity and aggressive behaviour in pigs

    PubMed Central

    2010-01-01

    Background Stress, elicited for example by aggressive interactions, has negative effects on various biological functions including immune defence, reproduction, growth, and, in livestock, on product quality. Stress response and aggressiveness are mutually interrelated and show large interindividual variation, partly attributable to genetic factors. In the pig little is known about the molecular-genetic background of the variation in stress responsiveness and aggressiveness. To identify candidate genes we analyzed association of DNA markers in each of ten genes (CRH g.233C>T, CRHR1 c.*866_867insA, CRHBP c.51G>A, POMC c.293_298del, MC2R c.306T>G, NR3C1 c.*2122A>G, AVP c.207A>G, AVPR1B c.1084A>G, UCN g.1329T>C, CRHR2 c.*13T>C) related to the hypothalamic-pituitary-adrenocortical (HPA) axis, one of the main stress-response systems, with various stress- and aggression-related parameters at slaughter. These parameters were: physiological measures of the stress response (plasma concentrations of cortisol, creatine kinase, glucose, and lactate), adrenal weight (which is a parameter reflecting activity of the central branch of the HPA axis over time) and aggressive behaviour (measured by means of lesion scoring) in the context of psychosocial stress of mixing individuals with different aggressive temperament. Results The SNP NR3C1 c.*2122A>G showed association with cortisol concentration (p = 0.024), adrenal weight (p = 0.003) and aggressive behaviour (front lesion score, p = 0.012; total lesion score p = 0.045). The SNP AVPR1B c.1084A>G showed a highly significant association with aggressive behaviour (middle lesion score, p = 0.007; total lesion score p = 0.003). The SNP UCN g.1329T>C showed association with adrenal weight (p = 0.019) and aggressive behaviour (front lesion score, p = 0.029). The SNP CRH g.233C>T showed a significant association with glucose concentration (p = 0.002), and the polymorphisms POMC c.293_298del and MC2R c.306T>G with adrenal weight (p = 0

  17. Ethanol-induced hypogonadism is not dependent on activation of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Emanuele, N V; LaPaglia, N; Benefield, J; Emanuele, M A

    2001-11-01

    The well-characterized suppression of the male reproductive unit after ethanol (EtOH) exposure has been speculated to be partially due to activation of the hypothalamic-pituitary-adrenal (HPA) axis. The subsequent corticosterone elevation could result in hypogonadism via suppression of hypothalamic LHRH, pituitary LH, or a direct gonadal effect. To directly examine this possibility, adult male Sprague Dawley rats were either adrenalectomized (ADX) or sham ADX. The ADX animals were given low dose corticosterone via replacement pellet, resulting in a steady level of serum corticosterone. The sham ADX (adrenal intact) animals were implanted with placebo pellets. Half of both groups were then exposed to EtOH by I.P. injection on two consecutive days to mimic an acute binge-drinking model. The other half was given saline I.P., serving as controls. In the adrenal intact animals, EtOH caused the expected rise in corticosterone, and fall in luteinizing hormone (LH) and testosterone. In the ADX animals, where constant levels of corticosterone were maintained by pellet implantation, EtOH resulted in similar LH and testosterone reduction. These results suggest that suppression of the reproductive axis is independent of the activation of the HPA unit.

  18. UVB Activates Hypothalamic-Pituitary-Adrenal Axis in C57BL/6 Mice.

    PubMed

    Skobowiat, Cezary; Slominski, Andrzej T

    2015-06-01

    To test the hypothesis that UVB can activate the hypothalamic-pituitary-adrenal (HPA) axis, the shaved back skin of C57BL/6 mice was exposed to 400 mJ cm(-2) of UVB or was sham irradiated. After 12 and 24 hours of exposure, plasma, skin, brain, and adrenals were collected and processed to measure corticotropin-releasing hormone (CRH), urocortin (Ucn), β-endorphin (β-END), ACTH, and corticosterone (CORT) or the brain was fixed for immunohistochemical detection of CRH. UVB stimulated plasma levels of CRH, Ucn, β-END, ACTH, and CORT and increased skin expression of Ucn, β-END, and CORT at the gene and protein/peptide levels. UVB stimulated CRH gene and protein expression in the brain that was localized to the paraventricular nucleus of the hypothalamus. In adrenal glands, it increased mRNAs of melanocortin receptor type 2, steroidogenic acute regulatory protein (StAR), and gene coding of steroid 11β-hydroxylase (CYP11B1). Hypophysectomy abolished UVB stimulation of plasma, but not of skin CORT levels, and had no effect on UVB stimulation of CRH and Ucn levels in the plasma, demonstrating the requirement of an intact pituitary for the systemic effect. In conclusion, we identify mechanisms regulating body homeostasis by UVB through activation of the HPA axis that originate in the skin and require the pituitary for systemic effects. PMID:25317845

  19. Dissection of Glucocorticoid Receptor-mediated Inhibition of the Hypothalamic-pituitary-adrenal Axis by Gene Targeting in Mice

    PubMed Central

    Laryea, Gloria; Muglia, Lisa; Arnett, Melinda; Muglia, Louis J.

    2014-01-01

    Negative feedback regulation of glucocorticoid (GC) synthesis and secretion occurs through the function of glucocorticoid receptor (GR) at sites in the hypothalamic-pituitary-adrenal (HPA) axis, as well as in brain regions such as the hippocampus, prefrontal cortex, and sympathetic nervous system. This function of GRs in negative feedback coordinates basal glucocorticoid secretion and stress-induced increases in secretion that integrate GC production with the magnitude and duration of the stressor. This review describes the effects of GR loss along major sites of negative feedback including the entire brain, the paraventricular nucleus of the hypothalamus (PVN), and the pituitary. In genetic mouse models, we evaluate circadian regulation of the HPA axis, stress-stimulated neuroendocrine response and behavioral activity, as well as the integrated response of organism metabolism. Our analysis provides information on contributions of region-specific GR-mediated negative feedback to provide insight in understanding HPA axis dysregulation and the pathogenesis of psychiatric and metabolic disorders. PMID:25256348

  20. Molecular regulation of the hypothalamic-pituitary-adrenal axis in adult male guinea pigs after prenatal stress at different stages of gestation

    PubMed Central

    Kapoor, Amita; Leen, Jason; Matthews, Stephen G

    2008-01-01

    Studies in humans and animals have demonstrated that maternal stress during fetal development can lead to altered hypothalamic-pituitary-adrenal (HPA) axis function and behaviour postnatally. We have previously shown adult male guinea pigs that were born to mothers exposed to a stressor during the phase of rapid fetal brain growth (gestational days (GD) 50, 51 and 52; prenatal stress (PS)50) exhibit significantly increased basal plasma cortisol levels. In contrast, male guinea pig offspring whose mothers were exposed to stress later in gestation (GD60, 61 and 62; PS60) exhibited a significantly higher plasma cortisol response to activation of the HPA axis. In the present study, we hypothesized that the endocrine changes in HPA axis function observed in male guinea pig offspring would be reflected by altered molecular regulation of the HPA axis. Corticosteroid receptors in the hippocampus, hypothalamus and pituitary were measured, as well as corticotropin-releasing hormone (CRH), pro-opiomelanocortin (POMC) and adrenal enzymes in the paraventricular nucleus, pituitary and adrenal cortex, respectively, by in situ hybridization and Western blot. PS50 male offspring exhibited a significant reduction in glucocorticoid receptor (GR) mRNA (P <0.01) in the CA3 region of the hippocampus and significantly increased POMC mRNA (P <0.05) in the pituitary, consistent with the increase in basal HPA axis activity observed. In line with elevated activity of the HPA axis, both PS50 and PS60 male offspring exhibited significantly higher steroidogenic factor (SF)-1 (P <0.001) and melanocortin 2 receptor (MC2-R) mRNA (P <0.001) in the adrenal cortex. This study demonstrates that short periods of prenatal stress during critical windows of neuroendocrine development affect the expression of key regulators of HPA axis activity leading to the changes in endocrine function observed in prenatally stressed male offspring. Further, these changes are dependent on the timing of the maternal

  1. HPA axis and vagus nervous function are involved in impaired insulin secretion of MSG-obese rats.

    PubMed

    Miranda, Rosiane A; Torrezan, Rosana; de Oliveira, Júlio C; Barella, Luiz F; da Silva Franco, Claudinéia C; Lisboa, Patrícia C; Moura, Egberto G; Mathias, Paulo C F

    2016-07-01

    Neuroendocrine dysfunctions such as the hyperactivity of the vagus nerve and hypothalamus-pituitary-adrenal (HPA) axis greatly contribute to obesity and hyperinsulinemia; however, little is known about these dysfunctions in the pancreatic β-cells of obese individuals. We used a hypothalamic-obesity model obtained by neonatal treatment with monosodium l-glutamate (MSG) to induce obesity. To assess the role of the HPA axis and vagal tonus in the genesis of hypercorticosteronemia and hyperinsulinemia in an adult MSG-obese rat model, bilateral adrenalectomy (ADX) and subdiaphragmatic vagotomy (VAG) alone or combined surgeries (ADX-VAG) were performed. To study glucose-induced insulin secretion (GIIS) and the cholinergic insulinotropic process, pancreatic islets were incubated with different glucose concentrations with or without oxotremorine-M, a selective agonist of the M3 muscarinic acetylcholine receptor (M3AChR) subtype. Protein expression of M3AChR in pancreatic islets, corticosteronemia, and vagus nerve activity was also evaluated. Surgeries reduced 80% of the body weight gain. Fasting glucose and insulin were reduced both by ADX and ADX-VAG, whereas VAG was only associated with hyperglycemia. The serum insulin post-glucose stimulation was lower in all animals that underwent an operation. Vagal activity was decreased by 50% in ADX rats. In the highest glucose concentration, both surgeries reduced GIIS by 50%, whereas ADX-VAG decreased by 70%. Additionally, M3AChR activity was recovered by the individual surgeries. M3AChR protein expression was reduced by ADX. Both the adrenal gland and vagus nerve contribute to the hyperinsulinemia in the MSG model, although adrenal is more crucial as it appears to modulate parasympathetic activity and M3AChR expression in obesity.

  2. Cranial irradiation modulates hypothalamic-pituitary-adrenal axis activity and corticosteroid receptor expression in the hippocampus of juvenile rat.

    PubMed

    Velickovic, Natasa; Djordjevic, Ana; Drakulic, Dunja; Stanojevic, Ivana; Secerov, Bojana; Horvat, Anica

    2009-01-01

    Glucocorticoids, essential for normal hypothalamic-pituitary-adrenal (HPA) axis activity, exert their action on the hippocampus through two types of corticosteroid receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). Recent studies report that exposure of juvenile rats to cranial irradiation adversely affects HPA axis stability leading to its activation along with radiation- induced inflammation. This study was aimed to examine the acute effects of radiation on HPA axis activity and hippocampal corticosteroid receptor expression in 18-day-old rats. Since immobilization was part of irradiation procedure, both irradiated and sham-irradiated animals were exposed to this unavoidable stress. Our results demonstrate that the irradiated rats exhibited different pattern of corticosteroid receptor expression and hormone levels compared to respective controls. These differences included upregulation of GR protein in the hippocampus with a concomitant elevation of GR mRNA and an increase in circulating level of corticosterone. In addition, the expression of MR, both at the level of protein and gene expression, was not altered. Taken together, this study demonstrates that cranial irradiation in juvenile rats leads to enhanced HPA axis activity and increased relative GR/MR ratio in hippocampus. The present paper intends to show that neuroendocrine response of normal brain tissue to localized irradiation comprise both activation of HPA axis and altered corticosteroid receptor balance, probably as consequence of innate immune activation.

  3. Hypothalamic-pituitary-adrenal axis responses of horses to therapeutic riding program: effects of different riders.

    PubMed

    Fazio, Esterina; Medica, Pietro; Cravana, Cristina; Ferlazzo, Adriana

    2013-06-13

    In order to determine whether therapeutic riding could result in higher levels of stress than recreational riding, hypothalamic-pituitary-adrenal (HPA) axis response was evaluated in six horses by monitoring circulating β-endorphin, ACTH and cortisol concentrations. Horses were already accustomed to be trained both for therapy and riding school activity since 2004. Intervention consisted of 60-minute therapeutic sessions, two times per week for 6weeks with different riders: disabled and recreational riders (session A and B respectively). The therapeutic riders' group (A) consisted of six children with psychomotor disabilities; the recreational riders' group (B) consisted of six healthy children without any previous horse riding experience. Horses were asked to perform the same gaits and exercises at all sessions, both with disabled and healthy users. The statistical analysis showed that during both sessions the mean basal β-endorphin and ACTH levels of horses did not show any significant changes, while the one way RM-ANOVA showed significant effects of sessions A on the cortisol (F=11.50; P<0.01) levels. Horses submitted to sessions A showed lower cortisol levels both at 5min (P<0.001) and at 30min (P<0.005) after therapeutic sessions than those after session B. Results suggest that in tested horses and for the variables settled, HPA axis was less responsive to disabled than healthy, recreational riders. Among the endocrine responses, cortisol was one of the indicators of HPA axis stress response. PMID:23684906

  4. Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Newby, Elizabeth A; Myers, Dean A; Ducsay, Charles A

    2015-09-01

    In utero, hypoxia is a significant yet common stress that perturbs homeostasis and can occur due to preeclampsia, preterm labor, maternal smoking, heart or lung disease, obesity, and high altitude. The fetus has the extraordinary capacity to respond to stress during development. This is mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis and more recently explored changes in perirenal adipose tissue (PAT) in response to hypoxia. Obvious ethical considerations limit studies of the human fetus, and fetal studies in the rodent model are limited due to size considerations and major differences in developmental landmarks. The sheep is a common model that has been used extensively to study the effects of both acute and chronic hypoxia on fetal development. In response to high-altitude-induced, moderate long-term hypoxia (LTH), both the HPA axis and PAT adapt to preserve normal fetal growth and development while allowing for responses to acute stress. Although these adaptations appear beneficial during fetal development, they may become deleterious postnatally and into adulthood. The goal of this review is to examine the role of the HPA axis in the convergence of endocrine and metabolic adaptive responses to hypoxia in the fetus.

  5. Hypothalamic-pituitary-adrenal axis responses of horses to therapeutic riding program: effects of different riders.

    PubMed

    Fazio, Esterina; Medica, Pietro; Cravana, Cristina; Ferlazzo, Adriana

    2013-06-13

    In order to determine whether therapeutic riding could result in higher levels of stress than recreational riding, hypothalamic-pituitary-adrenal (HPA) axis response was evaluated in six horses by monitoring circulating β-endorphin, ACTH and cortisol concentrations. Horses were already accustomed to be trained both for therapy and riding school activity since 2004. Intervention consisted of 60-minute therapeutic sessions, two times per week for 6weeks with different riders: disabled and recreational riders (session A and B respectively). The therapeutic riders' group (A) consisted of six children with psychomotor disabilities; the recreational riders' group (B) consisted of six healthy children without any previous horse riding experience. Horses were asked to perform the same gaits and exercises at all sessions, both with disabled and healthy users. The statistical analysis showed that during both sessions the mean basal β-endorphin and ACTH levels of horses did not show any significant changes, while the one way RM-ANOVA showed significant effects of sessions A on the cortisol (F=11.50; P<0.01) levels. Horses submitted to sessions A showed lower cortisol levels both at 5min (P<0.001) and at 30min (P<0.005) after therapeutic sessions than those after session B. Results suggest that in tested horses and for the variables settled, HPA axis was less responsive to disabled than healthy, recreational riders. Among the endocrine responses, cortisol was one of the indicators of HPA axis stress response.

  6. Fetal endocrine and metabolic adaptations to hypoxia: the role of the hypothalamic-pituitary-adrenal axis

    PubMed Central

    Newby, Elizabeth A.; Myers, Dean A.

    2015-01-01

    In utero, hypoxia is a significant yet common stress that perturbs homeostasis and can occur due to preeclampsia, preterm labor, maternal smoking, heart or lung disease, obesity, and high altitude. The fetus has the extraordinary capacity to respond to stress during development. This is mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis and more recently explored changes in perirenal adipose tissue (PAT) in response to hypoxia. Obvious ethical considerations limit studies of the human fetus, and fetal studies in the rodent model are limited due to size considerations and major differences in developmental landmarks. The sheep is a common model that has been used extensively to study the effects of both acute and chronic hypoxia on fetal development. In response to high-altitude-induced, moderate long-term hypoxia (LTH), both the HPA axis and PAT adapt to preserve normal fetal growth and development while allowing for responses to acute stress. Although these adaptations appear beneficial during fetal development, they may become deleterious postnatally and into adulthood. The goal of this review is to examine the role of the HPA axis in the convergence of endocrine and metabolic adaptive responses to hypoxia in the fetus. PMID:26173460

  7. Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats.

    PubMed

    Xu, Dan; Zhang, Benjian; Liang, Gai; Ping, Jie; Kou, Hao; Li, Xiaojun; Xiong, Jie; Hu, Dongcai; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-01-01

    Epidemiological investigations have shown that fetuses with intrauterine growth retardation (IUGR) are susceptible to adult metabolic syndrome. Clinical investigations and experiments have demonstrated that caffeine is a definite inducer of IUGR, as children who ingest caffeine-containing food or drinks are highly susceptible to adult obesity and hypertension. Our goals for this study were to investigate the effect of prenatal caffeine ingestion on the functional development of the fetal hippocampus and the hypothalamic-pituitary-adrenal (HPA) axis and to clarify an intrauterine HPA axis-associated neuroendocrine alteration induced by caffeine. Pregnant Wistar rats were intragastrically administered 20, 60, and 180 mg/kg · d caffeine from gestational days 11-20. The results show that prenatal caffeine ingestion significantly decreased the expression of fetal hypothalamus corticotrophin-releasing hormone. The fetal adrenal cortex changed into slight and the expression of fetal adrenal steroid acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc), as well as the level of fetal adrenal endogenous corticosterone (CORT), were all significantly decreased after caffeine treatment. Moreover, caffeine ingestion significantly increased the levels of maternal and fetal blood CORT and decreased the expression of placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2). Additionally, both in vivo and in vitro studies show that caffeine can downregulate the expression of fetal hippocampal 11β-HSD-2, promote the expression of 11β-hydroxysteroid dehydrogenase 1 and glucocorticoid receptor (GR), and enhance DNA methylation within the hippocampal 11β-HSD-2 promoter. These results suggest that prenatal caffeine ingestion inhibits the development of the fetal HPA axis, which may be associated with the fetal overexposure to maternal glucocorticoid and activated glucocorticoid metabolism in the fetal hippocampus. These results will be beneficial in

  8. BuShenYiQi Granule Inhibits Atopic Dermatitis via Improving Central and Skin Hypothalamic -Pituitary -Adrenal Axis Function

    PubMed Central

    Kong, Lingwen; Wu, Jingfeng; Lin, Yanhua; Wang, Genfa; Wang, Jia; Liu, Jiaqi; Chen, Meixia; Du, Xin; Sun, Jing; Lin, Jinpei; Dong, Jingcheng

    2015-01-01

    Background Dysfunction of central and skin Hypothalamic-Pituitary-Adrenal (HPA) axis play important roles in pathogenesis of atopic dermatitis (AD). Our previous studies showed that several Chinese herbs could improve HPA axis function. In this study, we evaluated the anti-inflammatory effects of BuShenYiQi granule (BSYQ), a Chinese herbs formula, in AD mice and explored the effective mechanism from regulation of HPA axis. Methods The ovalbumin (OVA) induced AD mice model were established and treated with BSYQ. We evaluated dermatitis score and histology analysis of dorsal skin lesions, meanwhile, serum corticosterone (CORT), adrenocorticotropic hormone (ACTH), corticotropin-releasing hormone (CRH) and inflammatory cytokines were determined by ELISA. The changes of CRH/proopiomelanocortin(POMC) axis elements, corresponding functional receptors and crucial genes of glucocorticosteroidogenesis in the skin were measured by quantitative real-time PCR and western blot, respectively. Results The symptoms and pathological changes in skin of AD mice were significantly improved and several markers of inflammation and allergy descended obviously after BSYQ treatment. We found that AD mice had insufficient central HPA tone, but these conditions were markedly improved after BSYQ treatment. The AD mice also showed a disturbed expression of skin HPA. In lesion skin of AD mice, the mRNA and protein expressions of CRH decreased significantly, on the contrary, POMC and cytochrome P450 side-chain cleavage enzyme (CYP11A1) increased markedly, meanwhile, NR3C1 (mouse GR), CRHR2 and 11-hydroxylase type 1(CYP11B1) were reduced locally. Most of these tested indexes were improved after BSYQ treatment. Conclusions AD mice displayed the differential expression pattern of central and skin HPA axis and BSYQ treatment significantly alleviated the symptoms of AD mice and presented anti-inflammatory and anti-allergic effects via regulating the expression of central and skin HPA axis. PMID

  9. Short-term safety assessment of clobetasol propionate 0.05% shampoo: hypothalamic-pituitary-adrenal axis suppression, atrophogenicity, and ocular safety in subjects with scalp psoriasis.

    PubMed

    Andres, Philippe; Poncet, Michel; Farzaneh, Sidou; Soto, Pascale

    2006-04-01

    Clobetasol propionate is known to be a very effective treatment for psoriasis; however, its use is limited by potent corticosteroid class related side effects such as hypothalamic-pituitary-adrenal (HPA) axis suppression and atrophogenicity. The aim of this single-center, parallel group, randomized study was to assess the HPA axis suppression potential, atrophogenicity, and ocular tolerability of clobetasol propionate shampoo in 26 patients with scalp psoriasis. Suitable subjects were treated once daily for 4 weeks with clobetasol propionate shampoo, to be rinsed off after 15 minutes or with a leave-on clobetasol propionate gel. The study demonstrated that clobetasol propionate shampoo did not lead to HPA axis suppression or to skin atrophy. Conversely, the gel led to HPA axis suppression and a decrease in skin thickness. Neither formulation had an impact on ocular safety. Despite the short contact application time, the clobetasol propionate shampoo provides similar efficacy results to the gel.

  10. [ACTIVITY OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS OF PRENATALLY STRESSED MALE RATS IN EXPERIMENTAL MODEL OF DEPRESSION].

    PubMed

    Ordyan, N E; Pivina, S G; Rakitskaya, V V; Akulova, V K

    2016-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis activity changes were examined in the adult, prenatally stressed male rats in the experimental depression model--the paradigm of "learned helplessness". It was shown that in males descending from intact mothers a depressive-like state was accompanied by an increase in HPA activity. The expression of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) increases, coupled with a rise in plasma levels of ACTH and corticosterone as well as in adrenal weight. At the same time in males born from mothers stressed during the last week of pregnancy we observed a decrease in activity of both the central (hypothalamus) and the peripheral (adrenal cortex) parts of regulation of this hormonal axis similar to that revealed for these animals in our previous study in "stress-restress" paradigm. It is concluded that prenatal stress modifies the sensitivity of animals to the inescapable intense stress impact, which manifests itself in a specific pattern of the HPA axis activity after stress load. PMID:27220240

  11. Characterization of the hypothalamic-pituitary-adrenal axis response to atrazine and metabolites in the female rat.

    PubMed

    Fraites, Melanie J P; Cooper, Ralph L; Buckalew, Angela; Jayaraman, Saro; Mills, Lesley; Laws, Susan C

    2009-11-01

    Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diamino-s-chlorotriazine (DACT), on the HPA axis in the Long-Evans female rat. A single oral gavage administration of 75 mg/kg ATR or 60.2 mg/kg DIA (a dose equimolar to the applied ATR dose) during the morning of proestrus resulted in significant, acute increases in circulating adrenocorticotropic hormone (ACTH), corticosterone, and progesterone. Oral doses of ATR or DIA were given daily over the course of the 4-day ovarian cycle starting on the day of vaginal estrus, resulted in a similar, dose-responsive activation of the HPA axis. The increase in ACTH, corticosterone, and progesterone by these compounds was of a similar magnitude to that produced by 5-min restraint stress. Single or multiple oral exposures to DACT, on the other hand, did not significantly alter pituitary-adrenal hormone release. These results were observed despite plasma levels of DACT being higher than any other metabolite at the time of hormone measurement. Overall, circulating metabolite concentrations following equimolar dosing were much higher than those observed after ATR administration. Additional studies indicated that the activation of the HPA axis by oral exposure to ATR and DIA was not due simply to the stimulation of gastrointestinal afferents. Similar responses were observed in rats which received an oral dose of ATR following bilateral subdiaphramatic vagotomy and following intravenous administration of DIA in jugular vein catheterized animals. We conclude that ATR and the metabolite DIA significantly activate the HPA axis following oral exposure in the female rat. Activation of this endocrine axis by these chlorotriazines could contribute to the induced changes of female reproductive function reported previously.

  12. Inter-relation between autonomic and HPA axis activity in children and adolescents.

    PubMed

    Rotenberg, Sivan; McGrath, Jennifer J

    2016-05-01

    Stress research in youth typically considers either the autonomic nervous system or HPA axis. However, these systems are highly coordinated and physically interconnected. We examined whether the inter-relation between cardio-autonomic and HPA axis measures was better associated with perceived stress than their singular associations. Children and adolescents (N=201) collected saliva samples to measure cortisol (AUCAG, AUCI, maximum), wore an electrocardiogram monitor for 24h to derive heart rate variability (HRV; LF, HF, LF/HF ratio), and completed the Perceived Stress Scale. The interaction between sympathovagal modulation (LF, LF/HF ratio) and cortisol awakening response (AUCAG, AUCI, maximum) explained significantly greater variance in perceived stress than either stress system alone. Higher sympathovagal modulation combined with higher cortisol awakening response was associated with greater perceived stress. Findings suggest that the inter-relation between cardio-autonomic and HPA axis activity may advance our understanding of how stress impacts health.

  13. Does trauma cause lasting changes in HPA-axis functioning in healthy individuals?

    PubMed

    Klaassens, Ellen R; van Veen, Tineke; Zitman, Frans G

    2008-01-01

    Although the majority of people who are exposed to traumatic events do not develop psychopathology, trauma has often been associated with increased vulnerability to psychiatric disorders. In addition, alterations in the HPA-axis have been demonstrated in patients with trauma-related psychiatric disorders. We hypothesize that trauma causes dysregulation of the HPA-axis. Therefore, we will compare HPA-axis functioning of traumatized and non-traumatized healthy individuals from the same gender and age from two categories: military and railroad personnel. In addition, a group of women with a history of childhood trauma was included. We will investigate for the putative role of attachment style and psychological resilience factors such as coping. In this article, we present the rationale for this study.

  14. Inter-relation between autonomic and HPA axis activity in children and adolescents.

    PubMed

    Rotenberg, Sivan; McGrath, Jennifer J

    2016-05-01

    Stress research in youth typically considers either the autonomic nervous system or HPA axis. However, these systems are highly coordinated and physically interconnected. We examined whether the inter-relation between cardio-autonomic and HPA axis measures was better associated with perceived stress than their singular associations. Children and adolescents (N=201) collected saliva samples to measure cortisol (AUCAG, AUCI, maximum), wore an electrocardiogram monitor for 24h to derive heart rate variability (HRV; LF, HF, LF/HF ratio), and completed the Perceived Stress Scale. The interaction between sympathovagal modulation (LF, LF/HF ratio) and cortisol awakening response (AUCAG, AUCI, maximum) explained significantly greater variance in perceived stress than either stress system alone. Higher sympathovagal modulation combined with higher cortisol awakening response was associated with greater perceived stress. Findings suggest that the inter-relation between cardio-autonomic and HPA axis activity may advance our understanding of how stress impacts health. PMID:26835595

  15. Maternal depression across the first years of life compromises child psychosocial adjustment; relations to child HPA-axis functioning.

    PubMed

    Apter-Levi, Yael; Pratt, Maayan; Vakart, Adam; Feldman, Michal; Zagoory-Sharon, Orna; Feldman, Ruth

    2016-02-01

    Maternal depression across the first years of life negatively impacts children's development. One pathway of vulnerability may involve functioning of the hypothalamic-pituitary-adrenal (HPA) axis. We utilize a community cohort of 1983 women with no comorbid risk repeatedly assessed for depression from birth to six years to form two groups; chronically depressed (N=40) and non-depressed (N=91) women. At six years, mother and child underwent psychiatric diagnosis, child salivary cortisol (CT) was assessed three times during a home-visit, mother-child interaction was videotaped, and child empathy was coded from behavioral paradigms. Latent Growth curve Model using Structural Equation Modeling (SEM) estimated the links between maternal depression and mother's negative parenting and three child outcomes; psychopathology, social withdrawal, and empathy as related to child CT baseline and variability. Depressed mothers displayed more negative parenting and their children showed more Axis-I psychopathology and social withdrawal. SEM analysis revealed that maternal depression was associated with reduced CT variability, which predicted higher child psychopathology and social withdrawal. Whereas all children exhibited similar initial levels of CT, children of controls reduced CT levels over time while children of depressed mothers maintained high, non-flexible levels. Mother negativity was related to lower initial CT levels, which predicted decreased empathy. Findings suggest that chronic maternal depression may compromise children's social-emotional adjustment by diminishing HPA-system flexibility as well as limiting the mother's capacity to provide attuned and predictable caregiving.

  16. Maternal depression across the first years of life compromises child psychosocial adjustment; relations to child HPA-axis functioning.

    PubMed

    Apter-Levi, Yael; Pratt, Maayan; Vakart, Adam; Feldman, Michal; Zagoory-Sharon, Orna; Feldman, Ruth

    2016-02-01

    Maternal depression across the first years of life negatively impacts children's development. One pathway of vulnerability may involve functioning of the hypothalamic-pituitary-adrenal (HPA) axis. We utilize a community cohort of 1983 women with no comorbid risk repeatedly assessed for depression from birth to six years to form two groups; chronically depressed (N=40) and non-depressed (N=91) women. At six years, mother and child underwent psychiatric diagnosis, child salivary cortisol (CT) was assessed three times during a home-visit, mother-child interaction was videotaped, and child empathy was coded from behavioral paradigms. Latent Growth curve Model using Structural Equation Modeling (SEM) estimated the links between maternal depression and mother's negative parenting and three child outcomes; psychopathology, social withdrawal, and empathy as related to child CT baseline and variability. Depressed mothers displayed more negative parenting and their children showed more Axis-I psychopathology and social withdrawal. SEM analysis revealed that maternal depression was associated with reduced CT variability, which predicted higher child psychopathology and social withdrawal. Whereas all children exhibited similar initial levels of CT, children of controls reduced CT levels over time while children of depressed mothers maintained high, non-flexible levels. Mother negativity was related to lower initial CT levels, which predicted decreased empathy. Findings suggest that chronic maternal depression may compromise children's social-emotional adjustment by diminishing HPA-system flexibility as well as limiting the mother's capacity to provide attuned and predictable caregiving. PMID:26610204

  17. Early life maternal separation stress augmentation of limbic epileptogenesis: the role of corticosterone and HPA axis programming.

    PubMed

    Koe, Amelia S; Salzberg, Michael R; Morris, Margaret J; O'Brien, Terence J; Jones, Nigel C

    2014-04-01

    Early life stress causes long-lasting effects on the limbic system that may be relevant to the development of mesial temporal lobe epilepsy (MTLE) and its associated psychopathology. Recent studies in rats suggest that maternal separation (MS), a model of early life stress, confers enduring vulnerability to amygdala kindling limbic epileptogenesis. However, the mechanisms underlying this remain unknown. Here, we tested whether hypothalamic-pituitary-adrenal (HPA) axis hyper-reactivity induced by MS - specifically the excessive secretion of corticosterone following a seizure - was involved in this vulnerability. In adult female rats subjected to MS from postnatal days 2-14, seizure-induced corticosterone responses were significantly augmented and prolonged for at least two hours post-seizure, compared to control early-handled (EH) rats. This was accompanied by reduced seizure threshold (p<0.05) and increased vulnerability to the kindling-induced progression of seizure duration (p<0.05) in MS rats. Pre-seizure treatment with the corticosterone synthesis inhibitor, metyrapone (MET) (50mg/kgsc) effectively blocked seizure-induced corticosterone responses. When delivered throughout kindling, MET treatment also reversed the MS-induced reduction in seizure threshold and the lengthened seizure duration back to levels of EH rats. These observations suggest that adverse early life environments induce a vulnerability to kindling epileptogenesis mediated by HPA axis hyper-reactivity, which could have relevance for the pathogenesis of MTLE.

  18. The stress-buffering effect of acute exercise: Evidence for HPA axis negative feedback.

    PubMed

    Zschucke, Elisabeth; Renneberg, Babette; Dimeo, Fernando; Wüstenberg, Torsten; Ströhle, Andreas

    2015-01-01

    According to the cross-stressor adaptation hypothesis, physically trained individuals show lower physiological and psychological responses to stressors other than exercise, e.g. psychosocial stress. Reduced stress reactivity may constitute a mechanism of action for the beneficial effects of exercise in maintaining mental health. With regard to neural and psychoneuroendocrine stress responses, the acute stress-buffering effects of exercise have not been investigated yet. A sample of highly trained (HT) and sedentary (SED) young men was randomized to either exercise on a treadmill at moderate intensity (60-70% VO2max; AER) for 30 min, or to perform 30 min of "placebo" exercise (PLAC). 90 min later, an fMRI experiment was conducted using an adapted version of the Montreal Imaging Stress Task (MIST). The subjective and psychoneuroendocrine (cortisol and α-amylase) changes induced by the exercise intervention and the MIST were assessed, as well as neural activations during the MIST. Finally, associations between the different stress responses were analysed. Participants of the AER group showed a significantly reduced cortisol response to the MIST, which was inversely related to the previous exercise-induced α-amylase and cortisol fluctuations. With regard to the sustained BOLD signal, we found higher bilateral hippocampus (Hipp) activity and lower prefrontal cortex (PFC) activity in the AER group. Participants with a higher aerobic fitness showed lower cortisol responses to the MIST. As the Hipp and PFC are brain structures prominently involved in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, these findings indicate that the acute stress-buffering effect of exercise relies on negative feedback mechanisms. Positive affective changes after exercise appear as important moderators largely accounting for the effects related to physical fitness.

  19. Neonatal sex hormones have 'organizational' effects on the hypothalamic-pituitary-adrenal axis of male rats.

    PubMed

    McCormick, C M; Furey, B F; Child, M; Sawyer, M J; Donohue, S M

    1998-02-10

    Sex hormones have activational effects on the hypothalamic-pituitary-adrenal (HPA) axis in adulthood: For example, corticosterone release is influenced by gonadal status. These experiments investigated whether sex hormones have organizational effects on the HPA axis of male rats: Do sex hormones have relatively permanent effects on its development? In adults, both neonatal (neoGDX) and adult gonadectomy (adult GDX) resulted in elevated corticosterone (CORT) levels in response to stress compared to intact rats. Five days of testosterone propionate (TP) replacement was not as effective at attenuating CORT levels in neoGDX rats as in adult GDX rats. Neonatal GDX elevated corticosterone binding globulin (CBG) levels, whereas adult GDX was without effect. In Experiment 2 the effects of neonatal gonadectomy and neonatal treatment with either TP, estradiol benzoate (EB), or oil vehicle was examined. Despite 14 days of hormone replacement, neoGDX showed elevated CORT levels in response to stress compared to all other groups. A single neonatal dose of TP or EB in neoGDX rats eliminated the increased responsiveness. Neonatal TP and EB were without effect in sham-operated rats. Plasma CBG levels were elevated in neoGDX groups regardless of neonatal hormone treatment. Corticosteroid receptor binding levels were examined in various brain areas and the pituitary in two groups most different in their androgen experience: NeoGDX and shams that did not receive treatments as adults. NeoGDX had lower levels of glucocorticoid receptor, and higher levels of mineralocorticoid receptor binding in the pituitary. No other receptor differences were found. These experiments suggest that neonatal sex hormones influence the sensitivity of the HPA axis to sex hormones in adulthood and, thus, that they have organizational effects in addition to activational effects on HPA function.

  20. Interferon-α effects on diurnal hypothalamic–pituitary–adrenal axis activity: relationship with proinflammatory cytokines and behavior

    PubMed Central

    Raison, CL; Borisov, AS; Woolwine, BJ; Massung, Breanne; Vogt, G; Miller, AH

    2012-01-01

    Interferon (IFN)-α has been used to investigate pathways by which innate immune cytokines influence the brain and behavior. Accordingly, the impact of IFN-α on diurnal secretion of hypothalamic–pituitary–adrenal (HPA) axis hormones was assessed in 33 patients eligible for treatment with IFN-α plus ribavirin for hepatitis C. In addition, the relationship between IFN-α-induced HPA axis changes and proinflammatory cytokines and behavior was examined. Plasma ACTH and cortisol as well as tumor necrosis factor (TNF)-α, interleukin-6 and their soluble receptors, were measured hourly between 0900 and 2100 hours at baseline and following approximately 12 weeks of either no treatment (n = 13) or treatment with IFN-α/ribavirin (n = 20). Plasma IFN-α was also measured at each visit. Depression and fatigue were assessed using the Montgomery–Asberg depression rating scale and the multidimensional fatigue inventory. Compared to no treatment, IFN-α/ribavirin administration was associated with significant flattening of the diurnal ACTH and cortisol slope and increased evening plasma ACTH and cortisol concentrations. Flattening of the cortisol slope and increases in evening cortisol were correlated with increases in depression (r = 0.38, P < 0.05 and r = 0.36, P < 0.05, respectively) and fatigue (r = 0.43, P < 0.05 and r = 0.49, P < 0.01, respectively). No relationship was found between immune and HPA axis measures, although increases in plasma IFN-α, TNF-α and soluble TNF-α receptor2 were independently correlated with behavioral endpoints. These data indicate that chronic exposure to innate immune cytokines may contribute to the altered diurnal HPA axis activity and behavior found in medically ill individuals. However, given the lack of correlation between HPA axis and immune measures, the mechanism by which chronic cytokine exposure influences HPA axis function remains to be determined. PMID:18521089

  1. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice.

    PubMed

    García, María Jesús; Martínez-Martos, José Manuel; Mayas, María Dolores; Carrera, María Pilar; De la Chica, Susana; Cortés, Pedro; Ramírez-Expósito, María Jesús

    2008-07-01

    The hypothalamus-pituitary-adrenal axis (HPA) participates in the maintenance of cardiovascular functions and in the control of blood pressure. By other hand, it is known that blood pressure regulation and HPA activity are affected by sex hormones. The aim of the present work is to analyze the influence of estradiol and progesterone on renin-angiotensin system (RAS)-regulating aminopeptidase A, aminopeptidase B and aminopeptidase N activities and vasopressin-degrading activity in the HPA axis of ovariectomized mice and ovariectomized mice treated subscutaneously with different doses of estradiol and progesterone. Our data suggest that in female mice, estradiol and progesterone influence RAS-regulating and vasopressin-degrading activities at different levels of the HPA axis.

  2. Influence of hormonal status on enkephalin-degrading aminopeptidase activity in the HPA axis of female mice.

    PubMed

    García-López, M J; Martínez-Martos, J M; Mayas, M D; Carrera, M P; Ramírez-Expósito, M J

    2005-04-01

    Opioids are involved in the regulation of hypothalamus-pituitary-adrenal (HPA) axis activity under physiological conditions. In the present work, we analyzed the influence of ovariectomy and estradiol (E), progesterone (P) or estradiol plus progesterone (E+P) replacement on soluble (S) and membrane-bound (MB) enkephalin-degrading aminopeptidase activity (EDA) in the HPA axis. Female mice (Balb/C) were distributed in 15 groups of 10 animals each: sham-operated controls (C), ovariectomized controls (OV-C), and ovariectomized mice treated with increasing doses of E (10, 20 or 40 mg/kg), P (100, 200 or 400 mg/kg) or E+P (10+100, 20+200 or 40+400 mg/kg). In hypothalamus, ovariectomy increased both S and MB EDA activities, whereas E replacement returned them to control levels, although MB EDA activity increased again after the replacement with 40 mg/kg E. P replacement increased S EDA activity, but returned MB EDA activity to control levels. The replacement of E+P returned both S and MB EDA activities to control levels, although MB EDA activity was lower than control values after the replacement with 10+100 mg/kg E+P. In pituitary, neither ovariectomy nor the replacement of E or E+P changed S EDA, although the highest concentrations of P increased S EDA activity. However, ovariectomy increased MB EDA and E replacement returned the activity to control or below control levels, depending on the concentration used. However, P administration returned the activity to control or below control levels depending on the concentration used, although 200 mg/kg P had no effects on MB EDA. E+P replacement returned pituitary MB EDA activity to control levels. In adrenal glands, ovariectomy did change either S or MB EDA. However, E, P or E+P replacement decreased S EDA activity in different degrees, depending of the dose administrated. No changes were detected in MB EDA after hormone replacement. These results indicate that female steroid hormones influence EDA activity at different

  3. [Activity of the hypothalamo-pituitary-adrenals axis in the Siberian tiger (Panthera tigris altaica) in captivity and in the wild, and their dynamics throughout the year].

    PubMed

    Naidenko, S V; Ivanov, E A; Lukarevskiĭ, V S; Hernandez-Blanko, J A; Sorokin, P A; Litvinov, M N; Kotliar, A K; Rozhnov, V V

    2011-01-01

    A noninvasive evaluation method of hypothalamo-pituitary-adrenals axis (HPA) activity in the Siberian tiger was verified. Comparison of the activity level of HPA in Siberian tigers in the wild and in captivity, and their alterations over the year was carried out. Significant seasonal deviations between activity levels of HPA in tigers in captivity were not found. In the wild, this level was significantly higher, reaching the maximum from November to January, which can be related with an unfavorable influence on tigers in low temperatures and deep snow cover.

  4. [Activity of the hypothalamo-pituitary-adrenals axis in the Siberian tiger (Panthera tigris altaica) in captivity and in the wild, and their dynamics throughout the year].

    PubMed

    Naidenko, S V; Ivanov, E A; Lukarevskiĭ, V S; Hernandez-Blanko, J A; Sorokin, P A; Litvinov, M N; Kotliar, A K; Rozhnov, V V

    2011-01-01

    A noninvasive evaluation method of hypothalamo-pituitary-adrenals axis (HPA) activity in the Siberian tiger was verified. Comparison of the activity level of HPA in Siberian tigers in the wild and in captivity, and their alterations over the year was carried out. Significant seasonal deviations between activity levels of HPA in tigers in captivity were not found. In the wild, this level was significantly higher, reaching the maximum from November to January, which can be related with an unfavorable influence on tigers in low temperatures and deep snow cover. PMID:21790001

  5. Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study.

    PubMed

    van der Knaap, Lisette J; Oldehinkel, Albertine J; Verhulst, Frank C; van Oort, Floor V A; Riese, Harriëtte

    2015-08-01

    Early life adversity and psychopathology are thought to be linked through HPA-axis deregulation. Changes in methylation levels of stress reactivity genes such as the glucocorticoid receptor gene (NR3C1) can be induced by adversity. Higher NR3C1 methylation levels have been associated with a reduced NR3C1 expression, possibly leading to impaired negative feedback regulation of the HPA-axis. In this study we tested whether methylation levels of NR3C1 were associated with HPA-axis regulation, operationalized as cortisol responses. In 361 adolescents (mean age 16.1, SD=0.6), salivary cortisol samples were collected before, during, and after a social stress task, from which response measures (cortisol activation and recovery) were calculated. Higher NR3C1 methylation levels were associated with a flattened cortisol recovery slope, indicating a delayed recovery time. Cortisol response activation was not associated with NR3C1 methylation. These results suggest that methylation of NR3C1 may impair negative feedback of the HPA-axis in adolescents.

  6. Diurnal expression of functional and clock-related genes throughout the rat HPA axis: system-wide shifts in response to a restricted feeding schedule.

    PubMed

    Girotti, Milena; Weinberg, Marc S; Spencer, Robert L

    2009-04-01

    The diurnal rhythm of glucocorticoid secretion depends on the suprachiasmatic (SCN) and dorsomedial (putative food-entrainable oscillator; FEO) nuclei of the hypothalamus, two brain regions critical for coordination of physiological responses to photoperiod and feeding cues, respectively. In both cases, time keeping relies upon diurnal oscillations in clock gene (per1, per2, and bmal) expression. Glucocorticoids may play a key role in synchronization of the rest of the body to photoperiod and food availability. Thus glucocorticoid secretion may be both a target and an important effector of SCN and FEO output. Remarkably little, however, is known about the functional diurnal rhythms of the individual components of the hypothalamic-pituitary-adrenal (HPA) axis. We examined the 24-h pattern of hormonal secretion (ACTH and corticosterone), functional gene expression (c-fos, crh, pomc, star), and clock gene expression (per1, per2 and bmal) in each compartment of the HPA axis under a 12:12-h light-dark cycle and compared with relevant SCN gene expression. We found that each anatomic component of the HPA axis has a unique circadian signature of functional and clock gene expression. We then tested the susceptibility of these measures to nonphotic entrainment cues by restricting food availability to only a portion of the light phase of a 12:12-h light-dark cycle. Restricted feeding is a strong zeitgeber that can dramatically alter functional and clock gene expression at all levels of the HPA axis, despite ongoing photoperiod cues and only minor changes in SCN clock gene expression. Thus the HPA axis may be an important mediator of the body entrainment to the FEO.

  7. Stressor-specific effects of sex on HPA axis hormones and activation of stress-related neurocircuitry.

    PubMed

    Babb, Jessica A; Masini, Cher V; Day, Heidi E W; Campeau, Serge

    2013-11-01

    Experiencing stress can be physically and psychologically debilitating to an organism. Women have a higher prevalence of some stress-related mental illnesses, the reasons for which are unknown. These experiments explore differential HPA axis hormone release in male and female rats following acute stress. Female rats had a similar threshold of HPA axis hormone release following low intensity noise stress as male rats. Sex did not affect the acute release, or the return of HPA axis hormones to baseline following moderate intensity noise stress. Sensitive indices of auditory functioning obtained by modulation of the acoustic startle reflex by weak pre-pulses did not reveal any sexual dimorphism. Furthermore, male and female rats exhibited similar c-fos mRNA expression in the brain following noise stress, including several sex-influenced stress-related regions. The HPA axis response to noise stress was not affected by stage of estrous cycle, and ovariectomy significantly increased hormone release. Direct comparison of HPA axis hormone release to two different stressors in the same animals revealed that although female rats exhibit robustly higher HPA axis hormone release after restraint stress, the same effect was not observed following moderate and high intensity loud noise stress. Finally, the differential effect of sex on HPA axis responses to noise and restraint stress cannot readily be explained by differential social cues or general pain processing. These studies suggest the effect of sex on acute stress-induced HPA axis hormone activity is highly dependent on the type of stressor.

  8. RasGRF1 regulates the hypothalamic-pituitary-adrenal axis specifically in early-adolescent female mice.

    PubMed

    Uzturk, Belkis Gizem; Jin, Shan-Xue; Rubin, Beverly; Bartolome, Christopher; Feig, Larry A

    2015-10-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 min/day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after one, three and five exposures is magnified approximately threefold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females.

  9. RasGRF1 Regulates the Hypothalamic-Pituitary-Adrenal Axis Specifically in Early-Adolescent Female Mice

    PubMed Central

    Uzturk, Belkis Gizem; Jin, Shan-xue; Rubin, Beverly; Bartolome, Christopher; Feig, Larry A.

    2015-01-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the induction and prolongation of a variety of psychiatric disorders. As such, much effort has been made to understand the molecular mechanisms involved in its control. However, the vast majority of the studies on the HPA axis have used adult animals, and among these the majority has used males. Here we show that in knockout mice lacking the guanine nucleotide exchange factor, RasGRF1, habituation to 30 minutes a day of restraint stress is markedly accelerated, such that these mice do not display elevated corticosterone levels or enhanced locomotion after 7 days of stress exposure, like WT mice do. Strikingly, this phenotype is present in early-adolescent female RasGRF1 knockout mice, but not in their early-adolescent male, mid-adolescent female, adult female or adult male counterparts. Moreover, not only is there a clear response to restraint stress in early-adolescent female RasGRF1 knockout mice, their response after 1, 3, and 5 exposures is magnified ~3-fold compared to WT mice. These findings imply that distinct mechanisms exist to regulate the HPA axis in early-adolescent females that involves RasGRF1. A full understanding of how RasGRF1 controls the HPA axis response to stress may be required to design effective strategies to combat stress-associated psychiatric disorders initiated in young females. PMID:26246084

  10. Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones.

    PubMed

    Stephens, Mary Ann C; Mahon, Pamela B; McCaul, Mary E; Wand, Gary S

    2016-04-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well-validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the

  11. Psoriasis severity and hypothalamic-pituitary-adrenal axis function: results from the CALIPSO study.

    PubMed

    Brunoni, A R; Santos, I S; Sabbag, C; Lotufo, P A; Benseñor, I M

    2014-12-01

    Psoriasis is a chronic inflammatory disease that significantly impacts life quality, being associated with stress and mental disorders. We investigated whether the activity of the hypothalamic-pituitary-adrenal (HPA) axis was associated with psoriasis severity, daily life stress and anxiety, and depressive symptoms. In this ancillary study, which was part of the CALIPSO (coronary artery calcium in psoriasis) study, saliva was collected from 102 patients with psoriasis immediately upon awakening, 30, and 60 min after awakening, at 2:00 pm and at bedtime (five time points) to determine salivary cortisol levels. We used Pearson's correlation coefficient to evaluate the association of clinical and psychopathological variables with HPA activity. We found a direct correlation between bedtime cortisol and psoriasis severity evaluated by the psoriasis area severity index (PASI; r=0.39, P<0.001). No correlations between other clinical and psychopathological variables or with other cortisol assessments were observed. The findings indicated that HPA dysfunction may be present in psoriasis, as bedtime cortisol was correlated with psoriasis severity. Our study is limited by the lack of a control group; therefore, we were not able to explore whether these cortisol values were different compared with a concurrent, healthy sample.

  12. Critical features of acute stress-induced cross-sensitization identified through the hypothalamic-pituitary-adrenal axis output.

    PubMed

    Belda, Xavier; Nadal, Roser; Armario, Antonio

    2016-01-01

    Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress-associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic-pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors. PMID:27511270

  13. Critical features of acute stress-induced cross-sensitization identified through the hypothalamic-pituitary-adrenal axis output

    PubMed Central

    Belda, Xavier; Nadal, Roser; Armario, Antonio

    2016-01-01

    Stress-induced sensitization represents a process whereby prior exposure to severe stressors leaves animals or humans in a hyper-responsive state to further stressors. Indeed, this phenomenon is assumed to be the basis of certain stress-associated pathologies, including post-traumatic stress disorder and psychosis. One biological system particularly prone to sensitization is the hypothalamic-pituitary-adrenal (HPA) axis, the prototypic stress system. It is well established that under certain conditions, prior exposure of animals to acute and chronic (triggering) stressors enhances HPA responses to novel (heterotypic) stressors on subsequent days (e.g. raised plasma ACTH and corticosterone levels). However, such changes remain somewhat controversial and thus, the present study aimed to identify the critical characteristics of the triggering and challenging stressors that affect acute stress-induced HPA cross-sensitization in adult rats. We found that HPA cross-sensitization is markedly influenced by the intensity of the triggering stressor, whereas the length of exposure mainly affects its persistence. Importantly, HPA sensitization is more evident with mild than strong challenging stressors, and it may remain unnoticed if exposure to the challenging stressor is prolonged beyond 15 min. We speculate that heterotypic HPA sensitization might have developed to optimize biologically adaptive responses to further brief stressors. PMID:27511270

  14. Metabolic syndrome, activity of the hypothalamic-pituitary-adrenal axis and inflammatory mediators in depressive disorder.

    PubMed

    Martinac, Marko; Pehar, Davor; Karlović, Dalibor; Babić, Dragan; Marcinko, Darko; Jakovljević, Miro

    2014-03-01

    Depression has been associated with various cardiovascular risk factors such as hypertension, obesity, atherogenic dyslipidemia and hyperglycemia. In depressive disorder, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and changes in the immune system have been observed. On the other hand, somatic diseases such as obesity, hyperlipidemia, hypertension and diabetes mellitus type 2 are now perceived as important comorbid conditions in patients with depression. The pathogenesis of the metabolic syndrome and depression is complex and poorly researched; however, it is considered that the interaction of chronic stress, psychotrauma, hypercotisolism and disturbed immune functions contribute to the development of these disorders. The aim of the study was to investigate the relationship between depression and metabolic syndrome regarding the HPA axis dysfunction and altered inflammatory processes. Literature search in Medline and other databases included articles written in English published between 1985 and 2012. Analysis of the literature was conducted using a systematic approach with the search terms such as depression, metabolic syndrome, inflammation, cytokines, glucocorticoids, cortisol, and HPA axis. In conclusion, the relationship between depression and metabolic syndrome is still a subject of controversy. Further prospective studies are required to clarify the possible causal relationship between depression and metabolic syndrome and its components. Furthermore, it is important to explore the possibility of a common biologic mechanism in the pathogenesis of these two disorders, in which special attention should be paid to the immune system function, especially the possible specific mechanisms by which cytokines can induce and maintain depressive symptoms and metabolic disorders. The data presented here emphasize the importance of recognition and treatment of depressive disorders with consequent reduction in the incidence of metabolic syndrome, but

  15. Disturbed immunoendocrine communication via the hypothalamo-pituitary-adrenal axis in murine lupus.

    PubMed

    Lechner, O; Hu, Y; Jafarian-Tehrani, M; Dietrich, H; Schwarz, S; Herold, M; Haour, F; Wick, G

    1996-12-01

    Immune reactions and mitogen stimulation of mammals and chickens lead to an increase of glucocorticoid (GC) plasma levels concomitant with the immune response. Interleukin (IL) 1, one of the most important glucocorticoid increasing factors produced by cells of the immune system, acts via the hypothalamo-pituitary-adrenal (HPA) axis. This pattern of immunoendocrine feedback communication is altered in autoimmune disease (AID) and represents a possible site of action for GC therapy. In the present study we investigated the role and possible underlying mechanisms of a disturbed immunoendocrine communication via the HPA axis in murine lupus. We analyzed the response to recombinant human (rhu) IL-1alpha in AID-prone mice [NZB, NZW, (NZB/NZW)F1, MRL/MP-lpr] in comparison to nonautoimmune, normal control mice (Swiss, C3H/HeJ, MRL/MP-+/+) at different levels of the HPA axis. To this end, we quantified the plasma levels of ACTH, corticosterone, and corticosterone-binding globulin (CBG) and determined various pathology parameters for autoimmunity. AID-prone mice produced nearly the same levels of plasma corticosterone after injection of rhu IL-1alpha as normal mice, but had baseline corticosterone levels consistently higher, thus resulting in significantly lower corticosterone increasing ratios. ACTH levels increased after rhu IL-1alpha injection, but there was no clearcut difference in the increasing ratios of AID-prone and normal strains. CBG levels showed no difference. As expected, there was a correlation of pathology parameters for autoimmunity and the altered immunomodulatory response to rhu IL-1alpha per group. On an individual basis, there was no such correlation. In conclusion, our results confirm the existence of a disturbed immunoendocrine communication in AID-prone mice. This disturbance clearly differs from individual to individual and also among different types of AID.

  16. Prematurity, Birth Weight, and Socioeconomic Status Are Linked to Atypical Diurnal Hypothalamic-Pituitary-Adrenal Axis Activity in Young Adults.

    PubMed

    Winchester, Suzy Barcelos; Sullivan, Mary C; Roberts, Mary B; Granger, Douglas A

    2016-02-01

    In a prospective, case-controlled longitudinal design, 180 preterm and fullterm infants who had been enrolled at birth participated in a comprehensive assessment battery at age 23. Of these, 149 young adults, 34 formerly full-term and 115 formerly preterm (22 healthy preterm, 48 with medical complications, 21 with neurological complications, and 24 small for gestational age) donated five saliva samples from a single day that were assayed for cortisol to assess diurnal variation of the hypothalamic-pituitary-adrenal (HPA) axis. Analyses were conducted to determine whether prematurity category, birth weight, and socioeconomic status were associated with differences in HPA axis function. Pre- and perinatal circumstances associated with prematurity influenced the activity of this environmentally sensitive physiological system. Results are consistent with the theory of Developmental Origins of Health and Disease and highlight a possible mechanism for the link between prematurity and health disparities later in life. PMID:26676400

  17. Hypothalamic-pituitary-adrenal axis activity in patients with pathological gambling and internet use disorder.

    PubMed

    Geisel, Olga; Panneck, Patricia; Hellweg, Rainer; Wiedemann, Klaus; Müller, Christian A

    2015-03-30

    Alterations in secretion of stress hormones within the hypothalamic-pituitary-adrenal (HPA) axis have repeatedly been found in substance-related addictive disorders. It has been suggested that glucocorticoids might contribute to the development and maintenance of substance use disorders by facilitatory effects on behavioral responses to substances of abuse. The objective of this pilot study was to investigate HPA axis activity in patients with non-substance-related addictive disorders, i.e. pathological gambling and internet use disorder. We measured plasma levels of copeptin, a vasopressin surrogate marker, adrenocorticotropic hormone (ACTH) and cortisol in male patients with pathological gambling (n=14), internet use disorder (n=11) and matched healthy controls for pathological gambling (n=13) and internet use disorder (n=10). Plasma levels of copeptin, ACTH and cortisol in patients with pathological gambling or internet use disorder did not differ among groups. However, cortisol plasma levels correlated negatively with the severity of pathological gambling as measured by the PG-YBOCS. Together with our findings of increased serum levels of brain-derived neurotrophic factor (BDNF) in pathological gambling but not internet use disorder, these results suggest that the pathophysiology of pathological gambling shares some characteristics with substance-related addictive disorders on a neuroendocrinological level, whereas those similarities could not be observed in internet use disorder.

  18. Hypothalamic-pituitary-adrenal axis function and the metabolic syndrome X of obesity.

    PubMed

    Gohil, B C; Rosenblum, L A; Coplan, J D; Kral, J G

    2001-07-01

    Obesity has negative health consequences related to fat distribution, particularly the central or visceral accumulation of fat. The major complications associated with visceral obesity, termed the "Metabolic Syndrome of Obesity," or "Syndrome X," are type II diabetes, hypertension, and dyslipidemia. As with certain mood disorders, the syndrome may be a consequence of neuroendocrine perturbations typically associated with chronic stress. Our work with bonnet macaque monkeys provides an animal model for the relationship between early stress, behavioral and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and Syndrome X. During their infant's first half-year, mothers face a variable foraging demand (VFD), in which ample food varies unpredictably in the difficulty of its acquisition, and the offspring show persistent abnormalities in systems known to modulate stress and affective regulation. Early work on the bonnet macaque noted the emergence of a sample of spontaneously obese subjects as they matured. Using the VFD model, the current study showed that there was a clear relationship between early cerebrospinal fluid corticotropin-releasing factor levels and subsequently measured body mass index, supporting the hypotheses regarding the interactive roles of early experience and HPA axis dysregulation in the ontogeny of both metabolic and mood disorders. PMID:15573024

  19. Neuropeptide Y (NPY) may integrate responses of hypothalamic feeding systems and the hypothalamo-pituitary-adrenal axis.

    PubMed

    Hanson, E S; Dallman, M F

    1995-04-01

    Neuropeptide Y (NPY) is a powerful stimulus to food intake in the rat. Exogenous NPY given into the third ventricle or into the paraventricular nucleus (PVN) of the hypothalamus stimulates both food consumption as well as the hypothalamus-pituitary-adrenal (HPA) axis. Presumably NPY activates the adrenocortical system through direct stimulation of CRF containing cells in the PVN. Food intake is also a major regulator of adrenocortical activation. Rhythms in HPA axis activity follow rhythms in food consumption, and rats that have been food deprived overnight have inhibited HPA axis responses to restraint stress and corticosteroid feedback the following morning. To investigate the interaction of NPY with both feeding and HPA axis activation three sets of experiments were performed: Animals fed ad lib were injected icv with NPY (2.5 micrograms) and allowed access to food or not post injection; animals were fasted overnight prior to NPY injection; finally, dose response experiments were performed to examine the relative sensitivities of feeding and HPA axis activation to exogenous NPY. Ad lib fed animals allowed access to food after NPY injection had slightly greater ACTH responses to NPY while glucocorticoid and insulin responses were not significantly different from ad lib fed animals not allowed access to food post injection. Animals allowed to eat post injection had significantly decreased food consumption the night following injection, however, total 24 h food consumption was not different between these animals and those given food 8 h post NPY injection. In overnight fasted animals NPY injections produced ACTH responses of equal magnitude to those in ad lib fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Perinatal malnutrition programs sympathoadrenal and hypothalamic-pituitary-adrenal axis responsiveness to restraint stress in adult male rats.

    PubMed

    Lesage, J; Dufourny, L; Laborie, C; Bernet, F; Blondeau, B; Avril, I; Bréant, B; Dupouy, J P

    2002-02-01

    In humans, an altered control of cortisol secretion was reported in adult men born with a low birth weight making the hypothalamic-pituitary-adrenal (HPA) axis a possible primary target of early life programming. In rats, we have recently shown that maternal food restriction during late pregnancy induces both an intrauterine growth retardation and an overexposure of fetuses to maternal corticosterone, which disturb the development of the HPA axis in offspring. The first aim of this work was to investigate, in adult male rats, whether perinatal malnutrition has long-lasting effects on the HPA axis activity during both basal and stressful conditions. Moreover, as the HPA axis and sympathetic nervous system are both activated by stress, the second aim of this work was to investigate, in these rats, the adrenomedullary catecholaminergic system under basal and stressful conditions. This study was conducted on 4-month-old male rats malnourished during their perinatal life and on age-matched control animals. Under basal conditions, perinatal malnutrition reduced body weight and plasma corticosteroid-binding globulin (CBG) level but increased mineralocorticoid receptor (MR) gene expression in CA1 hippocampal area. After 30 min of restraint, perinatally malnourished (PM) rats showed increased plasma noradrenaline, adrenocorticotropin hormone (ACTH) and corticosterone concentrations similarly as controls, but calculated plasma-free corticosterone concentration was significantly higher and adrenaline level lower than controls. During the phase of recovery, PM rats showed a rapid return of plasma ACTH and corticosterone concentrations to baseline levels in comparison with controls. These data suggest that in PM rats, an elevation of basal concentrations of corticosterone, in face of reduced CBG and probably increased hippocampal MR lead to a much larger impact of corticosterone on target cells that mediate the negative-feedback mechanism on the activities of both the HPA axis

  1. Activation of the hypothalamic-pituitary-adrenal axis following vestibular deafferentation in pigmented guinea pig.

    PubMed

    Gliddon, Catherine M; Darlington, Cynthia L; Smith, Paul F

    2003-02-28

    Twelve male pigmented guinea pigs underwent either a unilateral vestibular deafferentation (UVD) (n=6) or sham operation (n=6). Compared to the pre-operated salivary cortisol concentrations, the UVD operation resulted in a significant increase in night cortisol concentrations (P<0.05) and a significant interaction between the night cortisol concentration and time (P<0.05). There was no significant difference between the pre- and post-UVD morning salivary cortisol concentrations; nor between the pre- and post-sham morning or night salivary cortisol concentrations. This study suggests that the ocular-motor and postural syndrome is causing the activation of the hypothalamic-pituitary-adrenal (HPA) axis. PMID:12576192

  2. Decreased daytime illumination leads to anxiety-like behaviors and HPA axis dysregulation in the diurnal grass rat (Arvicanthis niloticus).

    PubMed

    Ikeno, Tomoko; Deats, Sean P; Soler, Joel; Lonstein, Joseph S; Yan, Lily

    2016-03-01

    The impact of ambient light on mood and anxiety is best exemplified in seasonal affective disorder, in which patients experience depression and anxiety in winter when there is less light in the environment. However, the brain mechanisms underlying light-dependent changes in affective state remain unclear. Our previous work revealed increased depression-like behaviors in the diurnal Nile grass rat (Arvicanthis niloticus) housed in a dim light-dark (dim-LD) cycle as compared to the controls housed in a bright light-dark (bright-LD) condition. As depression is often comorbid with anxiety and is associated with dysregulation of the body's stress response system, the present study examined the anxiety-like behaviors as well as indicators of the hypothalamic-pituitary-adrenal (HPA) axis functioning in the grass rats. Animals housed in dim-LD showed increased anxiety-like behaviors compared to bright-LD controls, as revealed by fewer entries and less time spent at the center in the open field test and more marbles buried during the marble-burying test. Following the marble-burying test, dim-LD animals showed higher plasma corticosterone (CORT) levels and hippocampal Fos expression. Although the daily CORT rhythm was comparable between bright-LD and dim-LD groups, the day/night variation of corticotropin-releasing hormone mRNA expression in the paraventricular nucleus was diminished in dim-LD animals. In addition, glucocorticoid receptor and mineralocorticoid receptor mRNA expression were higher in the hippocampus of dim-LD animals. The results suggest that in diurnal species, reduced daytime illumination can lead to increased anxiety-like behaviors and altered HPA axis functioning, providing insights into the link between decreased environmental illumination and negative emotion.

  3. Blunted HPA axis reactivity reveals glucocorticoid system dysbalance in a mouse model of high anxiety-related behavior.

    PubMed

    Sotnikov, Sergey; Wittmann, Anke; Bunck, Mirjam; Bauer, Sabrina; Deussing, Jan; Schmidt, Mathias; Touma, Chadi; Landgraf, Rainer; Czibere, Ludwig

    2014-10-01

    Depression and anxiety disorders are often characterized by altered hypothalamic-pituitary-adrenal (HPA) axis re-/activity. However, the presence of a molecular link between dysbalanced neuroendocrine regulation and psychopathologies is not yet fully established. Earlier, we reported that high (HAB), normal (NAB) and low (LAB) anxiety-related behavior mice express divergent anxiety-related and passive/active coping phenotypes. Here, we studied mechanisms that might contribute to the different HPA axis reactivity observed in HAB, NAB and LAB mice and their involvement in the regulation of anxiety-related behavior and passive/active coping style. We found that HAB mice respond with significantly reduced corticosterone (CORT) secretion to an acute stressful stimulus and a blunted response in the Dex/CRH test compared to NAB and LAB mice. At the molecular level, higher expression of the glucocorticoid receptor (GR/Nr3c1) and decreased corticotropin-releasing hormone receptor 1 (CRHR1) expression were observed in the pituitary of HAB mice. We further analyzed whether these stress mediators differed between the HAB, NAB and LAB lines in limbic system-associated brain regions and whether their interplay contributes to the phenotype. Interestingly, not only in the pituitary but also in almost all brain regions investigated, GR expression was significantly higher in HAB mice. In contrast, the amount of CORT in the brain structures analyzed was significantly lower in these animals. The expression of CRHR1 varied in the prefrontal cortex only. Since glucocorticoids regulate both GR and CRHR1, we treated HAB and NAB mice chronically with CORT. After 6 weeks of administration, reduced anxiety- and depression-like behaviors were observed in HAB mice, whereas increased anxiety was found in NABs. In both groups, GR, but not CRHR1, were significantly reduced. Taken together, our study proposes HAB mice as an animal model of simultaneous features of increased anxiety-related and

  4. Effects of halothane and methoxyflurane on the hypothalamic-pituitary-adrenal axis in rat.

    PubMed

    Karuri, A R; Engelking, L R; Kumar, M S

    1998-10-01

    Effects of acute exposure (2 h) to either 1.5% halothane or 0.5% methoxyflurane on chemical mediators of the hypothalamic-pituitary-adrenal (HPA) axis were evaluated in male Sprague-Dawley rats immediately after exposure, after the righting reflex (4 h), or 24 h postexposure. Effects of these anesthetics on hippocampal corticotropin releasing factor (CRF) were also evaluated. Methoxyflurane caused significant elevations in pituitary adrenocorticotropin hormone (ACTH)-like immunoreactivities in all three of the experiment's time groups, yet halothane failed to cause the same response immediately after exposure. Serum ACTH-like immunoreactivities were significantly elevated immediately after exposure to both anesthetics, but were not elevated at 4 and 24 h postexposure. Corticosterone (CORT)-like immunoreactivities were significantly elevated by halothane in all experimental groups, and in the 2- and 24-h groups following methoxyflurane exposure. Hippocampal CRF-like immunoreactivities remained unaffected by either anesthetic. Results indicate that a 2-h exposure to either halothane or methoxyflurane results in significant activation of the rat hypothalamic-pituitary-adrenal axis, and that the activation appears to be sustained over a 24-h period.

  5. Lack of specific association between panicogenic properties of caffeine and HPA-axis activation. A placebo-controlled study of caffeine challenge in patients with panic disorder.

    PubMed

    Masdrakis, Vasilios G; Markianos, Manolis; Oulis, Panagiotis

    2015-09-30

    A subgroup of patients with Panic Disorder (PD) exhibits increased sensitivity to caffeine administration. However, the association between caffeine-induced panic attacks and post-caffeine hypothalamic-pituitary-adrenal (HPA)-axis activation in PD patients remains unclear. In a randomized, double-blind, cross-over experiment, 19 PD patients underwent a 400-mg caffeine-challenge and a placebo-challenge, both administered in the form of instant coffee. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were assessed at both baseline and post-challenge. No patient panicked after placebo-challenge, while nine patients (47.3%) panicked after caffeine-challenge. Placebo administration did not result in any significant change in hormones' plasma levels. Overall, sample's patients demonstrated significant increases in ACTH, cortisol, and DHEAS plasma levels after caffeine administration. However, post-caffeine panickers and non-panickers did not differ with respect to the magnitude of the increases. Our results indicate that in PD patients, caffeine-induced panic attacks are not specifically associated with HPA-axis activation, as this is reflected in post-caffeine increases in ACTH, cortisol and DHEAS plasma levels, suggesting that caffeine-induced panic attacks in PD patients are not specifically mediated by the biological processes underlying fear or stress. More generally, our results add to the evidence that HPA-axis activation is not a specific characteristic of panic.

  6. Weight loss by calorie restriction versus bariatric surgery differentially regulates the HPA axis in male rats

    PubMed Central

    Grayson, Bernadette E.; Hakala-Finch, Andrew P.; Kekulawala, Melani; Laub, Holly; Egan, Ann E.; Ressler, Ilana B.; Woods, Stephen C.; Herman, James P.; Seeley, Randy J.; Benoit, Stephen C.; Ulrich-Lai, Yvonne M.

    2015-01-01

    Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in 5 groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n=7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n=11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n=11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n=11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n=12). Compared to Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentrations and increased hypothalamic corticotropin releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results suggest that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches. PMID:25238021

  7. Sexual dimorphism in the mouse hypothalamic-pituitary-adrenal axis function after endotoxin and insulin stresses during development.

    PubMed

    Spinedi, E; Chisari, A; Pralong, F; Gaillard, R C

    1997-01-01

    Bidirectional communication between the immune and the endocrine systems is now widely accepted as essential for the survival of the organism. Since a classical nonresponsive period of the hypothalamic-pituitary-adrenal (HPA) axis takes place shortly after birth and because endogenous sex hormones modulate immune function, the aim of the present work was to determine whether sex steroids regulate the PHA axis response to immune (bacterial, lipopolysaccharide, LPS) and nonimmune (insulin, INS) stressors in mice during development. For this purpose 7-, 15-, 30-, 45- and 60-day-old mice of both sexes were intraperitoneally injected with either vehicle alone (basal) or containing LPS (2 mg/kg body weight) or INS (12 IU/kg body weight). The animals were then killed by decapitation, 2 h or 45 min after LPS or INS, respectively. Plasma samples were assayed to measure corticosterone concentrations. The results indicated that: (a) there was a transient increase in basal plasma corticosterone levels during development, with a peak value at the juvenile age, regardless of sex; (b) a higher basal plasma corticosterone concentration in females than in males characterized the adult age; (c) the infantile age is a period of the HPA axis function nonresponsive to purely neuroendocrine but not to inflammatory stimuli; (d) during the juvenile age, females showed a hyporesponsive HPA axis to neurendocrine and immune stress, whereas male mice were fully unresponsive to both challenges; (e) animals of both sexes showed a maximal HPA axis response to purely neuroendocrine stress at the prepubertal age; this response to the immune stimulus was also maximal in 30-day-old males, while it was found in females after puberty (45-day-old mice); (f) sexual dimorphism in the HPA axis response to a purely neuroendocrine stimulus was found at 30 days of age or later, while this characteristic of the response to endotoxin was not present until puberty. These data clearly suggest that these are

  8. Effects of chronic oestrogen replacement on stress-induced activation of hypothalamic-pituitary-adrenal axis control pathways.

    PubMed

    Dayas, C V; Xu, Y; Buller, K M; Day, T A

    2000-08-01

    Oestrogen replacement therapy reportedly suppresses hypothalamic-pituitary-adrenal (HPA) axis responses to an emotional stressor in postmenopausal women. However, most studies in the rat suggest a facilitatory role for oestrogen in the control of HPA axis function. One explanation for this difference may be the regimen of oestrogen replacement: during oestrogen replacement therapy, oestrogen levels are low and constant whereas most animal studies examined the HPA axis response when oestrogen levels are rising. In the present study, we assessed HPA axis stress responses in mature ovariectomized rats after plasma oestrogen levels had been maintained at physiological levels for a prolonged period (25 or 100 pg/ml for 7 days). In the case of both an emotional stressor (noise) and a physical stressor (immune challenge by systemic interleukin-1beta administration), oestrogen replacement suppressed stress-related Fos-like immunolabelling, in hypothalamic neuroendocrine cells and plasma adrenocorticotropin hormone responses. From the present data, and past reports, it appears unlikely that these effects of oestrogen are due to a direct action on corticotropin-releasing factor or oxytocin cells. Therefore, to obtain some indication of oestrogen's possible site(s) of action, Fos-like immunolabelling was mapped in the amygdala and in brainstem catecholamine groups, which are neuronal populations demonstrating substantial evidence of involvement in the generation of HPA axis stress responses. In the amygdala, oestrogen replacement suppressed central nucleus responses to immune challenge, but not to noise. Amongst catecholamine cells, oestrogen replacement was more effective against responses to noise than immune challenge, suppressing A1 and A2 (noradrenergic) and C2 (adrenergic) responses to noise, but only A1 responses to immune challenge. These data suggest that, as in postmenopausal women on oestrogen replacement therapy, chronic low-level oestrogen replacement can

  9. Blunted Hypothalamo-pituitary Adrenal Axis Response to Predator Odor Predicts High Stress Reactivity

    PubMed Central

    Whitaker, Annie M.; Gilpin, Nicholas W.

    2015-01-01

    Individuals with trauma- and stress-related disorders exhibit increases in avoidance of trauma-related stimuli, heightened anxiety and altered neuroendocrine stress responses. Our laboratory uses a rodent model of stress that mimics the avoidance symptom cluster associated with stress-related disorders. Animals are classified as ‘Avoiders’ or Non-Avoiders' post-stress based on avoidance of predator-odor paired context. Utilizing this model, we are able to examine subpopulation differences in stress reactivity. Here, we used this predator odor model of stress to examine differences in anxiety-like behavior and hypothalamo-pituitary adrenal (HPA) axis function in animals that avoid a predator-paired context relative to those that do not. Rats were exposed to predator odor stress paired with a context and tested for avoidance (24 hours and 11 days), anxiety-like behavior (48 hours and 5 days) and HPA activation following stress. Control animals were exposed to room air. Predator odor stress produced avoidance in approximately 65% of the animals at 24 hours that persisted 11 days post-stress. Both Avoiders and Non-Avoiders exhibited heightened anxiety-like behavior at 48 hours and 5 days post-stress when compared to unstressed Controls. Non-Avoiders exhibited significant increases in circulating adrenocorticotropin hormone (ACTH) and corticosterone (CORT) concentrations immediately following predator odor stress compared to Controls and this response was significantly attenuated in Avoiders. There was an inverse correlation between circulating ACTH/CORT concentrations and avoidance, indicating that lower levels of ACTH/CORT predicted higher levels of avoidance. These results suggest that stress effects on HPA stress axis activation predict long-term avoidance of stress-paired stimuli, and builds on previous data showing the utility of this model for exploring the neurobiological mechanisms of trauma- and stress-related disorders. PMID:25824191

  10. Cocaine-induced increase in cortical acetylcholine release: interaction with the hypothalamo-pituitary-adrenal axis.

    PubMed

    Day, J C; Piazza, P V; Le Moal, M; Maccari, S

    1997-06-01

    An influence on drug-taking behaviours of the stress-related hypothalamo-pituitary-adrenal (HPA) axis and its final hormonal mediator, corticosterone, has previously been demonstrated. A role for cortically projecting cholinergic neurons in these behaviours can also be proposed. The experiments presented here examine the effect of the drug of abuse cocaine (15 mg/kg) on the release of acetylcholine (ACh) in the cortex of freely moving rats, using the technique of in vivo microdialysis. To assess a possible modulatory influence of the HPA axis via its final hormonal mediator corticosterone, the cocaine-induced effect on cortical ACh release in intact rats was compared to that in adrenalectomized (ADX) rats, which thus lacked their endogenous source of corticosterone, and in ADX rats in which the cocaine-induced corticosterone peak and/or the basal circadian concentrations of serum corticosterone were simulated by replacement treatments. The results reported here demonstrate that cortical ACh release is greatly increased by cocaine in intact rats; ADX prolongs the return to basal levels of cortical ACh, and the chronic replacement of circadian levels of corticosterone normalizes this effect. In contrast, during the plateau period of cocaine-induced increased cortical ACh release, where no effect of ADX is evident, rats with chronic replacement of corticosterone show an attenuated cocaine-induced cortical ACh release, and the acute replacement of the cocaine-induced corticosterone secretion further attenuates this response. These results demonstrate that cocaine stimulates cortically projecting cholinergic neurons, and that the HPA hormone corticosterone modulates this interaction in a complex manner which merits further investigation. PMID:9215695

  11. Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

    PubMed

    Li-Tempel, Ting; Larra, Mauro F; Winnikes, Ulrike; Tempel, Tobias; DeRijk, Roel H; Schulz, André; Schächinger, Hartmut; Meyer, Jobst; Schote, Andrea B

    2016-09-01

    The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity. PMID:27427534

  12. Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress.

    PubMed

    Li-Tempel, Ting; Larra, Mauro F; Winnikes, Ulrike; Tempel, Tobias; DeRijk, Roel H; Schulz, André; Schächinger, Hartmut; Meyer, Jobst; Schote, Andrea B

    2016-09-01

    The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity.

  13. Cumulative Effects of Prenatal Substance Exposure and Early Adversity on Foster Children's HPA-Axis Reactivity during a Psychosocial Stressor

    ERIC Educational Resources Information Center

    Fisher, Philip A.; Kim, Hyoun K.; Bruce, Jacqueline; Pears, Katherine C.

    2012-01-01

    Dysregulated hypothalamic-pituitary-adrenocortical (HPA) axis stress response has been reported among individuals with prenatal substance exposure and those with early adversity exposure. However, few researchers have examined the combined effects of these risk factors. Patterns of HPA reactivity among maltreated foster children with and without…

  14. Comparison of miRNA expression profiles in pituitary-adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure.

    PubMed

    Luo, Wei; Fang, Meixia; Xu, Haiping; Xing, Huijie; Fu, Jiangnan; Nie, Qinghua

    2016-01-01

    MicoRNAs (miRNAs), usually as gene regulators, participate in various biological processes, including stress responses. The hypothalamus-pituitary-adrenal axis (HPA axis) is an important pathway in regulating stress response. Although the mechanism that HPA axis regulates stress response has been basically revealed, the knowledge that miRNAs regulate stress response within HPA axis, still remains poor. The object of this study was to investigate the miRNAs in the pituitary and adrenal cortex that regulate chronic stress response with high-throughput sequencing. The pituitary and adrenal cortex of beagles and Chinese Field dogs (CFD) from a stress exposure group (including beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)) and a control group (including beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)), were selected for miRNA-seq comparisons. Comparisons, that were made in pituitary (including BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1 and BP2 vs. CFDP2) and adrenal cortex (including BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2), showed that a total of 39 and 18 common differentially expressed miRNAs (DE-miRNAs) (Total read counts > 1,000, Fold change > 2 & p-value < 0.001), that shared in at least two pituitary comparisons and at least two adrenal cortex comparisons, were detected separately. These identified DE-miRNAs were predicted for target genes, thus resulting in 3,959 and 4,010 target genes in pituitary and adrenal cortex, respectively. Further, 105 and 10 differentially expressed genes (DEGs) (Fold change > 2 & p-value < 0.05) from those target genes in pituitary and adrenal cortex were obtained separately, in combination with our previous corresponding transcriptome study. Meanwhile, in line with that miRNAs usually negatively regulated their target genes and the dual luciferase reporter assay, we finally

  15. Comparison of miRNA expression profiles in pituitary–adrenal axis between Beagle and Chinese Field dogs after chronic stress exposure

    PubMed Central

    Xu, Haiping; Xing, Huijie

    2016-01-01

    MicoRNAs (miRNAs), usually as gene regulators, participate in various biological processes, including stress responses. The hypothalamus–pituitary–adrenal axis (HPA axis) is an important pathway in regulating stress response. Although the mechanism that HPA axis regulates stress response has been basically revealed, the knowledge that miRNAs regulate stress response within HPA axis, still remains poor. The object of this study was to investigate the miRNAs in the pituitary and adrenal cortex that regulate chronic stress response with high-throughput sequencing. The pituitary and adrenal cortex of beagles and Chinese Field dogs (CFD) from a stress exposure group (including beagle pituitary 1 (BP1), CFD pituitary 1 (CFDP1), beagle adrenal cortex 1 (BAC1), CFD adrenal cortex 1 (CFDAC1)) and a control group (including beagle pituitary 2 (BP2), CFD pituitary 2 (CFDP2), beagle adrenal cortex 2 (BAC2), CFD adrenal cortex 2 (CFDAC2)), were selected for miRNA-seq comparisons. Comparisons, that were made in pituitary (including BP1 vs. BP2, CFDP1 vs. CFDP2, BP1 vs. CFDP1 and BP2 vs. CFDP2) and adrenal cortex (including BAC1 vs. BAC2, CFDAC1 vs. CFDAC2, BAC1 vs. CFDAC1 and BAC2 vs. CFDAC2), showed that a total of 39 and 18 common differentially expressed miRNAs (DE-miRNAs) (Total read counts > 1,000, Fold change > 2 & p-value < 0.001), that shared in at least two pituitary comparisons and at least two adrenal cortex comparisons, were detected separately. These identified DE-miRNAs were predicted for target genes, thus resulting in 3,959 and 4,010 target genes in pituitary and adrenal cortex, respectively. Further, 105 and 10 differentially expressed genes (DEGs) (Fold change > 2 & p-value < 0.05) from those target genes in pituitary and adrenal cortex were obtained separately, in combination with our previous corresponding transcriptome study. Meanwhile, in line with that miRNAs usually negatively regulated their target genes and the dual luciferase reporter assay, we

  16. Relational victimization, friendship, and adolescents’ hypothalamic–pituitary–adrenal axis responses to an in vivo social stressor

    PubMed Central

    CALHOUN, CASEY D.; HELMS, SARAH W.; HEILBRON, NICOLE; RUDOLPH, KAREN D.; HASTINGS, PAUL D.; PRINSTEIN, MITCHELL J.

    2014-01-01

    Adolescents’ peer experiences may have significant associations with biological stress-response systems, adding to or reducing allostatic load. This study examined relational victimization as a unique contributor to reactive hypothalamic–pituitary–adrenal (HPA) axis responses as well as friendship quality and behavior as factors that may promote HPA recovery following a stressor. A total of 62 adolescents (ages 12–16; 73% female) presenting with a wide range of life stressors and adjustment difficulties completed survey measures of peer victimization and friendship quality. Cortisol samples were collected before and after a lab-based interpersonally themed social stressor task to provide measures of HPA baseline, reactivity, and recovery. Following the stressor task, adolescents discussed their performance with a close friend; observational coding yielded measures of friends’ responsiveness. Adolescents also reported positive and negative friendship qualities. Results suggested that higher levels of adolescents’ relational victimization were associated with blunted cortisol reactivity, even after controlling for physical forms of victimization and other known predictors of HPA functioning (i.e., life stress or depressive symptoms). Friendship qualities (i.e., low negative qualities) and specific friendship behaviors (i.e., high levels of responsiveness) contributed to greater HPA regulation; however, consistent with theories of rumination, high friend responsiveness in the context of high levels of positive friendship quality contributed to less cortisol recovery. Findings extend prior work on the importance of relational victimization and dyadic peer relations as unique and salient correlates of adaptation in adolescence. PMID:25047287

  17. Relational victimization, friendship, and adolescents' hypothalamic-pituitary-adrenal axis responses to an in vivo social stressor.

    PubMed

    Calhoun, Casey D; Helms, Sarah W; Heilbron, Nicole; Rudolph, Karen D; Hastings, Paul D; Prinstein, Mitchell J

    2014-08-01

    Adolescents' peer experiences may have significant associations with biological stress-response systems, adding to or reducing allostatic load. This study examined relational victimization as a unique contributor to reactive hypothalamic-pituitary-adrenal (HPA) axis responses as well as friendship quality and behavior as factors that may promote HPA recovery following a stressor. A total of 62 adolescents (ages 12-16; 73% female) presenting with a wide range of life stressors and adjustment difficulties completed survey measures of peer victimization and friendship quality. Cortisol samples were collected before and after a lab-based interpersonally themed social stressor task to provide measures of HPA baseline, reactivity, and recovery. Following the stressor task, adolescents discussed their performance with a close friend; observational coding yielded measures of friends' responsiveness. Adolescents also reported positive and negative friendship qualities. Results suggested that higher levels of adolescents' relational victimization were associated with blunted cortisol reactivity, even after controlling for physical forms of victimization and other known predictors of HPA functioning (i.e., life stress or depressive symptoms). Friendship qualities (i.e., low negative qualities) and specific friendship behaviors (i.e., high levels of responsiveness) contributed to greater HPA regulation; however, consistent with theories of rumination, high friend responsiveness in the context of high levels of positive friendship quality contributed to less cortisol recovery. Findings extend prior work on the importance of relational victimization and dyadic peer relations as unique and salient correlates of adaptation in adolescence.

  18. Recovery of HPA Axis Function After Successful Gonadotropin-Induced Pregnancy and Delivery in a Woman With Panhypopituitarism

    PubMed Central

    Wang, Yi; Zhang, Qiongyue; Yang, Jianzhi; Zhao, Xiaolong; He, Min; Shou, Xuefei; Li, Shiqi; Li, Yiming; Wang, Yongfei; Ye, Hongying

    2015-01-01

    Abstract Hypopituitarism is defined as the partial or complete defect of anterior pituitary hormone secretion. Patients with hypopituitarism usually need life-long hormone replacement therapy. However, in this case, we report a patient with panhypopituitarism whose hypothalamus–pituitary–adrenal (HPA) axis function was completely recovered after pregnancy and delivery. In this case study, we reported the case management and conducted a review of literature to identify the possible mechanism of pituitary function recovery. The patient who suffered from secondary amenorrhea was found a nonfunctioning pituitary macroadenoma, and the hormone test showed serum cortisol, FT3, FT4, thyrotropic hormone, and prolactin were at normal range. After surgical removal of the tumor which invasion in the sellar region, the patient had panhypopituitarism confirmed by the routine hormone test. Though spontaneous pregnancy is impossible in female patients with panhypopituitarism, the patient was restored fertility by the help of artificial reproductive techniques. After the confirmation of the pregnancy, levothyroixine was increased to 75 μg daily and readjusted to 150 μg daily before delivery according to the monthly measurement thyroid function. Hydrocortisone 10 mg daily replaced cortisone acetate; the dose was increased according to the symptoms of morning sickness. A single stress dose of hydrocortisone (200 mg) was used before elective cesarean delivery and was tapered to the dose of 10 mg per day in 1 week. Levothyroixine was reduced to 75 μg daily after delivery. During follow-up, her hypothalamus–pituitary–adrenal (HPA) axis function was completely recovered. The peak serum cotisol level could increase to 19.08 μg/dL by insulin-induced hypoglycemia. However, growth hormone remained unresponsive to the insulin-tolerance test, and thyroid hormone still needed exogenous supplementation. Hormone replacement therapy needed closely followed by endocrinologist

  19. Developmental minocycline treatment reverses the effects of neonatal immune activation on anxiety- and depression-like behaviors, hippocampal inflammation, and HPA axis activity in adult mice.

    PubMed

    Majidi, Jafar; Kosari-Nasab, Morteza; Salari, Ali-Akbar

    2016-01-01

    Neonatal infection is associated with increased lifetime risk for neuropsychiatric disorders including anxiety and depression, with evidence showing that dysregulation of the hypothalamic-pituitary-adrenal-(HPA)-axis system may be partly responsible. Preclinical and clinical studies demonstrate that minocycline exhibits antidepressant effects through inhibition of microglial activation and anti-inflammatory actions, and of interest is that recent studies suggest that minocycline alleviates the behavioral abnormalities induced by early-life insults. The current study was designed to determine if developmental minocycline treatment attenuates the neonatal immune activation-induced anxiety- and depression-like symptoms and HPA-axis-dysregulation later in life. To this end, neonatal mice were treated to either lipopolysaccharide or saline on postnatal days (PND) 3-5, then dams during lactation (PND 6-20) and male offspring during adolescence (PND 21-40) received oral administration of minocycline or water via regular drinking bottles. Anxiety- and depression-like behaviors, HPA-axis-reactivity (corticosterone), and hippocampal inflammation (TNF-α and IL-1β) after exposure to stress were evaluated. The results indicated that neonatal immune activation resulted in increased anxiety and depression-like symptoms, HPA-axis-hyperactivity, and elevated the levels of TNF-α and IL-1β in the hippocampus in response to stress in adulthood. Interestingly, developmental minocycline treatment significantly reduced the abnormalities induced by neonatal inflammation in adult mice. In addition, minocycline, regardless of postnatal inflammation, did not have any detrimental effects on the above measured parameters. Considering that minocycline is currently under exploration as an alternative or adjunctive therapy for reducing the symptoms of neurological disorders, our findings suggest that minocycline during development can decrease the behavioral abnormalities induced by early

  20. Neonatal Amygdala Lesions Lead to Increased Activity of Brain CRF Systems and Hypothalamic-Pituitary-Adrenal Axis of Juvenile Rhesus Monkeys

    PubMed Central

    Stephens, Shannon B.Z.; Henry, Amy; Villarreal, Trina; Bachevalier, Jocelyne; Wallen, Kim; Sanchez, Mar M.

    2014-01-01

    The current study examined the long-term effects of neonatal amygdala (Neo-A) lesions on brain corticotropin-releasing factor (CRF) systems and hypothalamic-pituitary-adrenal (HPA) axis function of male and female prepubertal rhesus monkeys. At 12-months-old, CSF levels of CRF were measured and HPA axis activity was characterized by examining diurnal cortisol rhythm and response to pharmacological challenges. Compared with controls, Neo-A animals showed higher cortisol secretion throughout the day, and Neo-A females also showed higher CRF levels. Hypersecretion of basal cortisol, in conjunction with blunted pituitary-adrenal responses to CRF challenge, suggest HPA axis hyperactivity caused by increased CRF hypothalamic drive leading to downregulation of pituitary CRF receptors in Neo-A animals. This interpretation is supported by the increased CRF CSF levels, suggesting that Neo-A damage resulted in central CRF systems overactivity. Neo-A animals also exhibited enhanced glucocorticoid negative feedback, as reflected by an exaggerated cortisol suppression following dexamethasone administration, indicating an additional effect on glucocorticoid receptor (GR) function. Together these data demonstrate that early amygdala damage alters the typical development of the primate HPA axis resulting in increased rather than decreased activity, presumably via alterations in central CRF and GR systems in neural structures that control its activity. Thus, in contrast to evidence that the amygdala stimulates both CRF and HPA axis systems in the adult, our data suggest an opposite, inhibitory role of the amygdala on the HPA axis during early development, which fits with emerging literature on “developmental switches” in amygdala function and connectivity with other brain areas. PMID:25143624

  1. Resveratrol Ameliorates the Anxiety- and Depression-Like Behavior of Subclinical Hypothyroidism Rat: Possible Involvement of the HPT Axis, HPA Axis, and Wnt/β-Catenin Pathway

    PubMed Central

    Ge, Jin-Fang; Xu, Ya-Yun; Qin, Gan; Cheng, Jiang-Qun; Chen, Fei-Hu

    2016-01-01

    Metabolic disease subclinical hypothyroidism (SCH) is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES) in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days. The rats’ plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic–pituitary–adrenal (HPA) activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment downregulated the elevated plasma thyroid-stimulating hormone concentration and the hypothalamic mRNA expression of thyrotropin-releasing hormone in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the open-field test, increased sucrose preference in the sucrose preference test, and decreased immobility in the forced swimming test compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels, and the hypothalamic corticotrophin-releasing hormone mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment upregulated the relative ratio of phosphorylated-GSK3β (p-GSK3β)/GSK3β and protein levels of p-GSK3β, cyclin D1, and c-myc, while downregulating the relative ratio of phosphorylated-β-catenin (p-β-catenin)/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by downregulating hyperactivity of the HPA axis and regulating both the HPT axis and the

  2. Resveratrol Ameliorates the Anxiety- and Depression-Like Behavior of Subclinical Hypothyroidism Rat: Possible Involvement of the HPT Axis, HPA Axis, and Wnt/β-Catenin Pathway.

    PubMed

    Ge, Jin-Fang; Xu, Ya-Yun; Qin, Gan; Cheng, Jiang-Qun; Chen, Fei-Hu

    2016-01-01

    Metabolic disease subclinical hypothyroidism (SCH) is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES) in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days. The rats' plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic-pituitary-adrenal (HPA) activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment downregulated the elevated plasma thyroid-stimulating hormone concentration and the hypothalamic mRNA expression of thyrotropin-releasing hormone in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the open-field test, increased sucrose preference in the sucrose preference test, and decreased immobility in the forced swimming test compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels, and the hypothalamic corticotrophin-releasing hormone mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment upregulated the relative ratio of phosphorylated-GSK3β (p-GSK3β)/GSK3β and protein levels of p-GSK3β, cyclin D1, and c-myc, while downregulating the relative ratio of phosphorylated-β-catenin (p-β-catenin)/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by downregulating hyperactivity of the HPA axis and regulating both the HPT axis and the Wnt

  3. Resveratrol Ameliorates the Anxiety- and Depression-Like Behavior of Subclinical Hypothyroidism Rat: Possible Involvement of the HPT Axis, HPA Axis, and Wnt/β-Catenin Pathway.

    PubMed

    Ge, Jin-Fang; Xu, Ya-Yun; Qin, Gan; Cheng, Jiang-Qun; Chen, Fei-Hu

    2016-01-01

    Metabolic disease subclinical hypothyroidism (SCH) is closely associated with depression-like behavior both in human and animal studies, and our previous studies have identified the antidepressant effect of resveratrol (RES) in stressed rat model. The aim of this study was to investigate whether RES would manifest an antidepressant effect in SCH rat model and explore the possible mechanism. A SCH rat model was induced by hemi-thyroid electrocauterization, after which the model rats in the RES and LT4 groups received a daily intragastric injection of RES at the dose of 15 mg/kg or LT4 at the dose of 60 μg/kg for 16 days. The rats' plasma concentrations of thyroid hormones were measured. Behavioral performance and hypothalamic-pituitary-adrenal (HPA) activity were evaluated. The protein expression levels of the Wnt/β-catenin in the hippocampus were detected by western blot. The results showed that RES treatment downregulated the elevated plasma thyroid-stimulating hormone concentration and the hypothalamic mRNA expression of thyrotropin-releasing hormone in the SCH rats. RES-treated rats showed increased rearing frequency and distance in the open-field test, increased sucrose preference in the sucrose preference test, and decreased immobility in the forced swimming test compared with SCH rats. The ratio of the adrenal gland weight to body weight, the plasma corticosterone levels, and the hypothalamic corticotrophin-releasing hormone mRNA expression were reduced in the RES-treated rats. Moreover, RES treatment upregulated the relative ratio of phosphorylated-GSK3β (p-GSK3β)/GSK3β and protein levels of p-GSK3β, cyclin D1, and c-myc, while downregulating the relative ratio of phosphorylated-β-catenin (p-β-catenin)/β-catenin and expression of GSK3β in the hippocampus. These findings suggest that RES exerts anxiolytic- and antidepressant-like effect in SCH rats by downregulating hyperactivity of the HPA axis and regulating both the HPT axis and the Wnt

  4. Examining the role of endogenous orexins in hypothalamus-pituitary-adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat.

    PubMed

    Steiner, Michel A; Sciarretta, Carla; Brisbare-Roch, Catherine; Strasser, Daniel S; Studer, Rolf; Jenck, Francois

    2013-04-01

    The orexin neuropeptide system regulates wakefulness and contributes to physiological and behavioral stress responses. Moreover, a role for orexins in modulating hypothalamus-pituitary-adrenal (HPA) axis activity has been proposed. Brain penetrating dual orexin receptor (OXR) antagonists such as almorexant decrease vigilance and have emerged as a novel therapeutic class for the treatment of insomnia. Almorexant was used here as a pharmacological tool to examine the role of endogenous orexin signaling in HPA axis endocrine function under natural conditions. After confirming the expression of prepro-orexin and OXR-1 and OXR-2 mRNA in hypothalamus, pituitary and adrenal glands, the effects of systemic almorexant were investigated on peripheral HPA axis hormone release in the rat under baseline, stress and pharmacological challenge conditions. Almorexant did not alter basal or stress-induced corticosterone release despite affecting wake and sleep stages (detected by radiotelemetric electroencephalography/electromyography) during the stress exposure. Moreover, almorexant did not affect the release of adrenocorticotropin (ACTH) and corticosterone at different time points along the diurnal rhythm, nor corticotrophin-releasing hormone (CRH)- and ACTH-stimulated neuroendocrine responses, measured in vivo under stress-free conditions. These results illustrate that dual OXR antagonists, despite modulating stress-induced wakefulness, do not interfere with endocrine HPA axis function in the rat. They converge to suggest that endogenous orexin signaling plays a minor role in stress hormone release under basal conditions and under challenge.

  5. Developmental aspects of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Wintour, E M

    1984-06-01

    The ovine fetal adrenal cortex and pituitary are functional secretory organs by the end of the first third of gestation (term is 142-152 days). By half-way through gestation the zona glomerulosa is mature morphologically, more than 80% of the aldosterone in fetal blood is of fetal adrenal origin, but conventional stimuli, for example, increased plasma K+ or angiotensin II, do not increase aldosterone secretion until near term. The zona fasciculata is immature histologically, relatively unresponsive to ACTH, and contributes less than 10% of the cortisol in fetal blood between 100 and 120 days of gestation. After this time the zona fasciculata cells begin to mature, to respond to ACTH and to produce an increasing proportion of the cortisol in fetal blood. A functional relationship between hypothalamus-pituitary-adrenal cortex matures over the last fifth of gestation. It is hypothesized that cortisol exerts a local effect in maturation of fetal zona fasciculata cells, such that low concentrations of ACTH have increasingly larger effects on growth and secretion of the fasciculata and that the level of negative feedback by cortisol on the hypothalamic-pituitary axis is reset. The analogy is drawn between the changes in gonadotrophin and gonadal hormones which culminates in puberty in man and the changes in ACTH and cortisol which culminate in parturition in sheep.

  6. The involvement of noradrenergic mechanisms in the suppressive effects of diazepam on the hypothalamic-pituitary-adrenal axis activity in female rats

    PubMed Central

    Švob Štrac, Dubravka; Muck-Šeler, Dorotea; Pivac, Nela

    2012-01-01

    Aim To elucidate the involvement of noradrenergic system in the mechanism by which diazepam suppresses basal hypothalamic-pituitary-adrenal (HPA) axis activity. Methods Plasma corticosterone and adrenocorticotropic hormone (ACTH) levels were determined in female rats treated with diazepam alone, as well as with diazepam in combination with clonidine (α2-adrenoreceptor agonist), yohimbine (α2-adrenoreceptor antagonist), alpha-methyl-p-tyrosine (α-MPT, an inhibitor of catecholamine synthesis), or reserpine (a catecholamine depleting drug) and yohimbine. Results Diazepam administered in a dose of 2.0 mg/kg suppressed basal HPA axis activity, ie, decreased plasma corticosterone and ACTH levels. Pretreatment with clonidine or yohimbine failed to affect basal plasma corticosterone and ACTH concentrations, but abolished diazepam-induced inhibition of the HPA axis activity. Pretreatment with α-MPT, or with a combination of reserpine and yohimbine, increased plasma corticosterone and ACTH levels and prevented diazepam-induced inhibition of the HPA axis activity. Conclusion The results suggest that α2-adrenoreceptors activity, as well as intact presynaptic noradrenergic function, are required for the suppressive effect of diazepam on the HPA axis activity. PMID:22661134

  7. Prenatal exposure to interleukin-6 results in hypertension and increased hypothalamic-pituitary-adrenal axis activity in adult rats.

    PubMed

    Samuelsson, Anne-Maj; Ohrn, Iris; Dahlgren, Jovanna; Eriksson, Elias; Angelin, Bo; Folkow, Björn; Holmäng, Agneta

    2004-11-01

    During pregnancy, systemic inflammatory responses induce cytokines that may stress the fetus and contribute to cardiovascular and neuroendocrine dysfunction in adulthood. We evaluated the effects of early and late prenatal exposure to IL-6 on mean systolic arterial pressure (MSAP) and hypothalamic-pituitary-adrenal (HPA) axis regulation in male and female rats at 5-24 wk of age. MSAP and ACTH and corticosterone levels were measured basally and in response to a novel environment, immobilization stress, and stimulation with corticotropin-releasing factor (CRF) and ACTH. In addition, mRNA expression and protein levels of glucocorticoid receptor, mineralocorticoid receptor, CRF receptor type 1, and CRF were estimated in brain areas thought to mediate central effects of corticosteroids on the HPA axis and on central neuroendocrine regulation of MSAP. Both early and late prenatal IL-6 exposure led to hypertension, which was evident in females at 5 wk of age. In adult rats, basal ACTH and corticosterone levels were elevated, the responses to stress and stimulation tests were of extended duration, and circadian rhythm during the light period was flattened and reversed. Mineralocorticoid receptor and glucocorticoid receptor mRNA expression was reduced in the hippocampus, the CRF level was increased in the hypothalamus, and CRF receptor type 1 mRNA expression was increased in the pituitary. These findings suggest that fetal stress induced by prenatal exposure to IL-6 leads to hypertension and dysregulation of HPA axis activity during adulthood.

  8. The dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses the behavioral despair induced by stress in rats and modulates the HPA-axis.

    PubMed

    Navarria, Andrea; Tamburella, Alessandra; Iannotti, Fabio A; Micale, Vincenzo; Camillieri, Giovanni; Gozzo, Lucia; Verde, Roberta; Imperatore, Roberta; Leggio, Gian Marco; Drago, Filippo; Di Marzo, Vincenzo

    2014-09-01

    In recent years, several studies have explored the involvement of the deregulation of the hypothalamus-pituitary-adrenal (HPA) axis in the pathophysiology of stress-related disorders. HPA hyper-activation as a consequence of acute/chronic stress has been found to play a major role in the neurobiological changes that are responsible for the onset of such states. Currently available medications for depression, one of the most relevant stress-related disorders, present several limitations, including a time lag for treatment response and low rates of efficacy. N-Arachidonoylserotonin (AA-5-HT), a dual blocker at fatty acid amide hydrolase (FAAH, the enzyme responsible for the inactivation of the endocannabinoid anandamide) and transient receptor potential vanilloid type-1 channel (TRPV1), produces anxiolytic-like effects in mice. The present study was designed to assess the capability of AA-5-HT to reverse the behavioral despair following exposure to stress in rats and the role of the HPA-axis. Behavioral tasks were performed, and corticosterone and endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in selected brain areas critically involved in the pathophysiology of stress-related disorders (medial PFC and hippocampus) under basal and stress conditions, and in response to treatment with AA-5-HT. Our data show that AA-5-HT reverses the rat behavioral despair in the forced swim test under stress conditions, and this effect is associated with the normalization of the HPA-axis deregulation that follows stress application and only in part with elevation of anandamide levels. Blockade of FAAH and TRPV1 may thus represent a novel target to design novel therapeutic strategies for the treatment of stress-related disorders.

  9. Hypothalamic-pituitary-adrenal axis in the night eating syndrome.

    PubMed

    Birketvedt, Grethe S; Sundsfjord, Johan; Florholmen, Jon R

    2002-02-01

    The typical neuroendocrine characteristics of the night eating syndrome have previously been described as changes in the circadian rhythm by an attenuation in the nocturnal rise of the plasma concentrations of melatonin and leptin and an increased circadian secretion of cortisol. The aim of this study was to test the hypothesis that night eaters have an overexpressed hypothalamic-pituitary-adrenal axis with an attenuated response to stress. Five female subjects with the night-eating syndrome and five sex-, age-, and weight-matched controls performed a 120-min corticotropin-releasing hormone (CRH) test (100 microg iv). Blood samples were drawn intravenously for measurements of the plasma concentrations of ACTH and cortisol. The results showed that, in night eaters compared with controls, the CRH-induced ACTH and cortisol response was significantly decreased to 47 and 71%, respectively. In conclusion, disturbances in the hypothalamic-pituitary-adrenal axis with an attenuated ACTH and cortisol response to CRH were found in subjects with night-eating syndrome.

  10. Vaginal hypersensitivity and hypothalamic-pituitary-adrenal axis dysfunction as a result of neonatal maternal separation in female mice.

    PubMed

    Pierce, A N; Ryals, J M; Wang, R; Christianson, J A

    2014-03-28

    Early life stress can permanently alter functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the stress response and influences the perception of pain. Chronic pelvic pain patients commonly report having experienced childhood neglect or abuse, which increases the likelihood of presenting with comorbid chronic pain and/or mood disorders. Animal models of neonatal stress commonly display enhanced anxiety-like behaviors, colorectal hypersensitivity, and disruption of proper neuro-immune interactions in adulthood. Here, we tested the hypothesis that early life stress impacts vaginal sensitivity by exposing mice to neonatal maternal separation (NMS) for 3h/day during the first two (NMS14) or three (NMS21) postnatal weeks. As adults, female mice underwent vaginal balloon distension (VBD), which was also considered an acute stress. Before or after VBD, mice were assessed for anxiety-like behavior, hindpaw sensitivity, and changes in gene and protein expression related to HPA axis function and regulation. NMS21 mice displayed significantly increased vaginal sensitivity compared to naïve mice, as well as significantly reduced anxiety-like behavior at baseline, which was heightened following VBD. NMS21 mice exhibited significant thermal and mechanical hindpaw hypersensitivity at baseline and following VBD. NMS14 mice displayed no change in anxiety-like behavior and only exhibited significantly increased hindpaw mechanical and thermal sensitivity following VBD. Centrally, a significant decrease in negative regulation of the HPA axis was observed in the hypothalamus and hippocampus of NMS21 mice. Peripherally, NMS and VBD affected the expression of inflammatory mediators in the vagina and bladder. Corticotropin-releasing factor (CRF) receptor and transient receptor potential (TRP) channel protein expression was also significantly, and differentially, affected in vagina, bladder, and colon by both NMS and VBD. Together these data indicate that NMS

  11. Short periods of prenatal stress affect growth, behaviour and hypothalamo-pituitary-adrenal axis activity in male guinea pig offspring.

    PubMed

    Kapoor, Amita; Matthews, Stephen G

    2005-08-01

    Prenatal stress can have profound long-term influences on physiological function throughout the course of life. We hypothesized that focused periods of moderate prenatal stress at discrete time points in late gestation have differential effects on hypothalamo-pituitary-adrenal (HPA) axis function in adult guinea pig offspring, and that changes in HPA axis function will be associated with modification of anxiety-related behaviour. Pregnant guinea pigs were exposed to a strobe light for 2 h on gestational days (GD) 50, 51, 52 (PS50) or 60, 61, 62 (PS60) (gestation length approximately 70 days). A control group was left undisturbed throughout pregnancy. Behaviour was assessed in male offspring on postnatal day (PND)25 and PND70 by measurement of ambulatory activity and thigmotaxis (wall-seeking behaviour) in a novel open field environment. Subsequent to behavioural testing, male offspring were cannulated (PND75) to evaluate basal and activated HPA axis function. Body weight was significantly decreased in adult PS50 and PS60 offspring and this effect was apparent soon after weaning. The brain-to-body-weight ratio was significantly increased in adult PS50 males. Basal plasma cortisol levels were elevated in PS50 male offspring throughout the 24 h sampling period compared with controls. In response to an ACTH challenge and to exposure to an acute stressor, PS60 male offspring exhibited elevated plasma cortisol responses. Plasma testosterone concentrations were strikingly decreased in PS50 offspring. Thigmotaxis in the novel environment was increased in PS50 male offspring at PND25 and PND70, suggesting increased anxiety in these animals. In conclusion, prenatal stress during critical windows of neuroendocrine development programs growth, HPA axis function, and stress-related behaviour in adult male guinea pig offspring. Further, the nature of the effect is dependant on the timing of the maternal stress during pregnancy.

  12. Gender differences in the effect of prenatal alcohol exposure on the hypothalamic-pituitary-adrenal axis response to immune signals.

    PubMed

    Lee, S; Rivier, C

    1996-02-01

    Immature (3 week old) rat offspring of alcohol (E)-fed dams show a blunted ACTH response to immune signals such as interleukin-1 beta (IL-1 beta) and endotoxin (LPS). In contrast, mature offspring respond to physical stresses with an exaggerated activation of their hypothalamic-pituitary-adrenal (HPA) axis. The present work was aimed at determining if there was a differential influence of prenatal E exposure on the HPA axis responses to various stressors or if, alternatively, sexual maturation modified these responses. When administered IL-1 beta at 5 weeks age, E-treated intact male offspring released less ACTH, compared to control (C) or pair-fed (PF) animals. However, they showed an augmented response to LPS and a local inflammatory process induced by turpentine injection. At this same age, intact E females secreted significantly more ACTH in response to IL-1 beta, LPS and turpentine, than C or PF offspring. By 9 weeks of age, both E males and E females exhibited larger (p < .05) ACTH responses to all three immune stimuli. In order to determine whether sex steroids modulate the influence of E in females, ovariectomy was done prior to puberty. This treatment decreased the difference in the ACTH released by E and C rats in response to IL-1 beta, LPS and turpentine. These results show that while immature rats exposed to E prenatally released less ACTH in response to cytokines than C or PF animals did, this response was qualitatively reversed after puberty. At that time, the larger amounts of ACTH secreted by E offspring, compared to the other groups, were reminiscent of the hyperactive response of the HPA axis when these offspring were exposed to physical stress. Interestingly, removal of circulating ovarian steroids prevented the influence of E from being exerted. This suggests the presence of a functional relationship between the pathways influenced by prenatal E and those influenced by female sex steroids, that are important in regulating the activity of the HPA

  13. Effects of mild calorie restriction on anxiety and hypothalamic–pituitary–adrenal axis responses to stress in the male rat

    PubMed Central

    Kenny, Rachel; Dinan, Tara; Cai, Guohui; Spencer, Sarah J.

    2014-01-01

    Abstract Chronic calorie restriction (CR) is one of the few interventions to improve longevity and quality of life in a variety of species. It also reduces behavioral indices of anxiety and influences some stress hormones under basal conditions. However, it is not known how CR influences hypothalamic–pituitary–adrenal (HPA) axis function or if those on a CR diet have heightened HPA axis responses to stress. We hypothesized elevated basal glucocorticoid levels induced by CR would lead to exacerbated HPA axis responses to the psychological stress, restraint, in the male rat. We first confirmed rats fed 75% of their normal calorie intake for 3 weeks were less anxious than ad libitum‐fed (AD) rats in the elevated plus maze test for anxiety. The anxiolytic effect was mild, with only grooming significantly attenuated in the open field and no measured behavior affected in the light/dark box. Despite elevated basal glucocorticoids, CR rats had very similar hormonal and central responses to 15‐min restraint to the AD rats. Both CR and AD rats responded to restraint stress with a robust increase in glucocorticoids that was resolved by 60 min. Both groups also showed robust neuronal activation in the paraventricular nucleus of the hypothalamus and in other stress‐ and feeding‐sensitive brain regions that was not substantially affected by calorie intake. Our findings thus demonstrate chronic mild CR is subtly anxiolytic and is not likely to affect HPA axis responses to psychological stress. These findings support research suggesting a beneficial effect of mild CR. PMID:24760519

  14. Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal axis-associated proteins

    PubMed Central

    Zuloaga, Damian G.; Siegel, Jessica A.; Acevedo, Summer F.; Agam, Maayan; Raber, Jacob

    2013-01-01

    Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or Saline from postnatal day (P) 11–20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR-immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and area occupied by vasopressin-immunoreactiviy in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin-immunoreactivity in the PVN, or GR-immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, area occupied by GR-immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin-immunoreactivity no longer differed from Saline controls. No effects of MA were found on oxytocin or GR-immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin-immunoreactivity and short-term effects on GR-immunoreactivity. PMID:23860125

  15. Changes in the maternal hypothalamic-pituitary-adrenal axis during the early puerperium may be related to the postpartum 'blues'.

    PubMed

    O'Keane, V; Lightman, S; Patrick, K; Marsh, M; Papadopoulos, A S; Pawlby, S; Seneviratne, G; Taylor, A; Moore, R

    2011-11-01

    Most women experience time-limited and specific mood changes in the days after birth known as the maternity blues (Blues). The maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes gradual changes during pregnancy because of an increasing production of placental corticotrophin-releasing hormone (CRH). The abrupt withdrawal of placental CRH at birth results in a re-equilibration of the maternal HPA axis in the days post-delivery. These changes may be involved in the aetiology of the Blues given the central role of the HPA axis in the aetiology of mood disorders in general, and in perinatal depression in particular. We aimed to test the novel hypothesis that the experience of the Blues may be related to increased secretion of hypothalamic adrenocorticotrophic hormone (ACTH) secretagogue peptides, after the reduction in negative-feedback inhibition on the maternal hypothalamus caused by withdrawal of placental CRH. We therefore examined hormonal changes in the HPA axis in the days after delivery in relation to daily mood changes: our specific prediction was that mood changes would parallel ACTH levels, reflecting increased hypothalamic peptide secretion. Blood concentrations of CRH, ACTH, cortisol, progesterone and oestriol were measured in 70 healthy women during the third trimester of pregnancy, and on days 1-6 post-delivery. Blues scores were evaluated during the postpartum days. Oestriol, progesterone and CRH levels fell rapidly from pregnancy up to day 6, whereas cortisol levels fell modestly. ACTH concentrations declined from pregnancy to day 3 post-delivery and thereafter increased up to day 6. Blues scores increased, peaking on day 5, and were positively correlated with ACTH; and negatively correlated with oestriol levels during the postpartum days, and with the reduction in CRH concentrations from pregnancy. These findings give indirect support to the hypothesis that the 'reactivation' of hypothalamic ACTH secretagogue peptides may be involved in the

  16. Hypothalamic-pituitary-adrenal axis and behavioral dysfunction following early binge-like prenatal alcohol exposure in mice.

    PubMed

    Wieczorek, Lindsay; Fish, Eric W; O'Leary-Moore, Shonagh K; Parnell, Scott E; Sulik, Kathleen K

    2015-05-01

    The range of defects that fall within fetal alcohol spectrum disorder (FASD) includes persistent behavioral problems, with anxiety and depression being two of the more commonly reported issues. Previous studies of rodent FASD models suggest that interference with hypothalamic-pituitary-adrenal (HPA) axis structure and/or function may be the basis for some of the prenatal alcohol (ethanol) exposure (PAE)-induced behavioral abnormalities. Included among the previous investigations are those illustrating that maternal alcohol treatment limited to very early stages of pregnancy (i.e., gestational day [GD]7 in mice; equivalent to the third week post-fertilization in humans) can cause structural abnormalities in areas such as the hypothalamus, pituitary gland, and other forebrain regions integral to controlling stress and behavioral responses. The current investigation was designed to further examine the sequelae of prenatal alcohol insult at this early time period, with particular attention to HPA axis-associated functional changes in adult mice. The results of this study reveal that GD7 PAE in mice causes HPA axis dysfunction, with males and females showing elevated corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels, respectively, following a 15-min restraint stress exposure. Males also showed elevated CORT levels following an acute alcohol injection of 2.0 g/kg, while females displayed blunted ACTH levels. Furthermore, analysis showed that anxiety-like behavior was decreased after GD7 PAE in female mice, but was increased in male mice. Collectively, the results of this study show that early gestational alcohol exposure in mice alters long-term HPA axis activity and behavior in a sexually dimorphic manner.

  17. A naturally hypersensitive glucocorticoid receptor elicits a compensatory reduction of hypothalamus–pituitary–adrenal axis activity early in ontogeny

    PubMed Central

    Muráni, Eduard; Ponsuksili, Siriluck; Jaeger, Alexandra; Görres, Andreas; Tuchscherer, Armin; Wimmers, Klaus

    2016-01-01

    We comprehensively characterized the effects of a unique natural gain-of-function mutation in the glucocorticoid receptor (GR), GRAla610Val, in domestic pigs to expand current knowledge of the phenotypic consequences of GR hypersensitivity. Cortisol levels were consistently reduced in one-week-old piglets, at weaning and in peripubertal age, probably due to a reduced adrenal capacity to produce glucocorticoids (GC), which was indicated by an adrenocortical thinning in GRAla610Val carriers. Adrenocorticotrophic hormone (ACTH) levels were significantly reduced in one-week-old piglets only. Expression analyses in peripubertal age revealed significant downregulation of hypothalamic expression of CRH and AVP, the latter only in females, and upregulation of hepatic expression of SERPINA6, by GRAla610Val. Transcriptional repression of proinflammatory genes in peripheral blood mononuclear cells (PBMCs) from GRAla610Val carriers was more sensitive to dexamethasone treatment ex vivo. However, no significant effects on growth, body composition, blood chemistry or cell counts were observed under baseline conditions. These results suggest that GRAla610Val-induced GR hypersensitivity elicits a compensatory reduction in endogenous, bioactive glucocorticoid levels via readjustment of the hypothalamus–pituitary–adrenal (HPA) axis early in ontogeny to maintain an adequate response, but carriers are more sensitive to exogenous GC. Therefore, GRAla610Val pigs represent a valuable animal model to explore GR-mediated mechanisms of HPA axis regulation and responses to glucocorticoid-based drugs. PMID:27440422

  18. Assessing behavioural effects of chronic HPA axis activation using conditional CRH-overexpressing mice.

    PubMed

    Dedic, Nina; Touma, Chadi; Romanowski, Cristoph P; Schieven, Marcel; Kühne, Claudia; Ableitner, Martin; Lu, Ailing; Holsboer, Florian; Wurst, Wolfgang; Kimura, Mayumi; Deussing, Jan M

    2012-07-01

    The corticotropin-releasing hormone (CRH) and its cognate receptors have been implicated in the pathophysiology of stress-related disorders. Hypersecretion of central CRH and elevated glucocorticoid levels, as a consequence of impaired feedback control, have been shown to accompany mood and anxiety disorders. However, a clear discrimination of direct effects of centrally hypersecreted CRH from those resulting from HPA axis activation has been difficult. Applying a conditional strategy, we have generated two conditional CRH-overexpressing mouse lines: CRH-COE ( Del ) mice overexpress CRH throughout the body, while CRH-COE ( APit ) mice selectively overexpress CRH in the anterior and intermediate lobe of the pituitary. Both mouse lines show increased basal plasma corticosterone levels and consequently develop signs of Cushing's syndrome. However, while mice ubiquitously overexpressing CRH exhibited increased anxiety-related behaviour, overexpression of CRH in the pituitary did not produce alterations in emotional behaviour. These results suggest that chronic hypercorticosteroidism alone is not sufficient to alter anxiety-related behaviour but rather that central CRH hyperdrive on its own or in combination with elevated glucocorticoids is responsible for the increase in anxiety-related behaviour. In conclusion, the generated mouse lines represent valuable animal models to study the consequences of chronic CRH overproduction and HPA axis activation.

  19. Psychological Stress and the Cutaneous Immune Response: Roles of the HPA Axis and the Sympathetic Nervous System in Atopic Dermatitis and Psoriasis.

    PubMed

    Hall, Jessica M F; Cruser, Desanges; Podawiltz, Alan; Mummert, Diana I; Jones, Harlan; Mummert, Mark E

    2012-01-01

    Psychological stress, an evolutionary adaptation to the fight-or-flight response, triggers a number of physiological responses that can be deleterious under some circumstances. Stress signals activate the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Elements derived from those systems (e.g., cortisol, catecholamines and neuropeptides) can impact the immune system and possible disease states. Skin provides a first line of defense against many environmental insults. A number of investigations have indicated that the skin is especially sensitive to psychological stress, and experimental evidence shows that the cutaneous innate and adaptive immune systems are affected by stressors. For example, psychological stress has been shown to reduce recovery time of the stratum corneum barrier after its removal (innate immunity) and alters antigen presentation by epidermal Langerhans cells (adaptive immunity). Moreover, psychological stress may trigger or exacerbate immune mediated dermatological disorders. Understanding how the activity of the psyche-nervous -immune system axis impinges on skin diseases may facilitate coordinated treatment strategies between dermatologists and psychiatrists. Herein, we will review the roles of the HPA axis and the sympathetic nervous system on the cutaneous immune response. We will selectively highlight how the interplay between psychological stress and the immune system affects atopic dermatitis and psoriasis. PMID:22969795

  20. Psychological Stress and the Cutaneous Immune Response: Roles of the HPA Axis and the Sympathetic Nervous System in Atopic Dermatitis and Psoriasis.

    PubMed

    Hall, Jessica M F; Cruser, Desanges; Podawiltz, Alan; Mummert, Diana I; Jones, Harlan; Mummert, Mark E

    2012-01-01

    Psychological stress, an evolutionary adaptation to the fight-or-flight response, triggers a number of physiological responses that can be deleterious under some circumstances. Stress signals activate the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Elements derived from those systems (e.g., cortisol, catecholamines and neuropeptides) can impact the immune system and possible disease states. Skin provides a first line of defense against many environmental insults. A number of investigations have indicated that the skin is especially sensitive to psychological stress, and experimental evidence shows that the cutaneous innate and adaptive immune systems are affected by stressors. For example, psychological stress has been shown to reduce recovery time of the stratum corneum barrier after its removal (innate immunity) and alters antigen presentation by epidermal Langerhans cells (adaptive immunity). Moreover, psychological stress may trigger or exacerbate immune mediated dermatological disorders. Understanding how the activity of the psyche-nervous -immune system axis impinges on skin diseases may facilitate coordinated treatment strategies between dermatologists and psychiatrists. Herein, we will review the roles of the HPA axis and the sympathetic nervous system on the cutaneous immune response. We will selectively highlight how the interplay between psychological stress and the immune system affects atopic dermatitis and psoriasis.

  1. Depletion of FKBP51 in female mice shapes HPA axis activity.

    PubMed

    Hoeijmakers, Lianne; Harbich, Daniela; Schmid, Bianca; Lucassen, Paul J; Wagner, Klaus V; Schmidt, Mathias V; Hartmann, Jakob

    2014-01-01

    Psychiatric disorders such as depressive disorders and posttraumatic stress disorder are a major disease burden worldwide and have a higher incidence in women than in men. However, the underlying mechanism responsible for the sex-dependent differences is not fully understood. Besides environmental factors such as traumatic life events or chronic stress, genetic variants contribute to the development of such diseases. For instance, variations in the gene encoding the FK506 binding protein 51 (FKBP51) have been repeatedly associated with mood and anxiety. FKBP51 is a negative regulator of the glucocorticoid receptor and thereby of the hypothalamic-pituitary-adrenal axis that also interacts with other steroid hormone receptors such as the progesterone and androgen receptors. Thus, the predisposition of women to psychiatric disorders and the interaction of female hormones with FKBP51 and the glucocorticoid receptor implicate a possible difference in the regulation of the hypothalamic-pituitary-adrenal axis in female FKBP51 knockout (51KO) mice. Therefore, we investigated neuroendocrine, behavioural and physiological alterations relevant to mood disorders in female 51KO mice. Female 51KOs and wild type littermates were subjected to various behavioural tests, including the open field, elevated plus maze and forced swim test. The neuroendocrine profile was investigated under basal conditions and in response to an acute stressor. Furthermore, we analysed the mRNA expression levels of the glucocorticoid receptor and corticotrophin release hormone in different brain regions. Overall, female 51KO mice did not display any overt behavioural phenotype under basal conditions, but showed a reduced basal hypothalamic-pituitary-adrenal axis activity, a blunted response to, and an enhanced recovery from, acute stress. These characteristics strongly overlap with previous studies in male 51KO mice indicating that FKBP51 shapes the behavioural and neuroendocrine phenotype independent of

  2. Depletion of FKBP51 in Female Mice Shapes HPA Axis Activity

    PubMed Central

    Hoeijmakers, Lianne; Harbich, Daniela; Schmid, Bianca; Lucassen, Paul J.; Wagner, Klaus V.; Schmidt, Mathias V.; Hartmann, Jakob

    2014-01-01

    Psychiatric disorders such as depressive disorders and posttraumatic stress disorder are a major disease burden worldwide and have a higher incidence in women than in men. However, the underlying mechanism responsible for the sex-dependent differences is not fully understood. Besides environmental factors such as traumatic life events or chronic stress, genetic variants contribute to the development of such diseases. For instance, variations in the gene encoding the FK506 binding protein 51 (FKBP51) have been repeatedly associated with mood and anxiety. FKBP51 is a negative regulator of the glucocorticoid receptor and thereby of the hypothalamic–pituitary–adrenal axis that also interacts with other steroid hormone receptors such as the progesterone and androgen receptors. Thus, the predisposition of women to psychiatric disorders and the interaction of female hormones with FKBP51 and the glucocorticoid receptor implicate a possible difference in the regulation of the hypothalamic–pituitary–adrenal axis in female FKBP51 knockout (51KO) mice. Therefore, we investigated neuroendocrine, behavioural and physiological alterations relevant to mood disorders in female 51KO mice. Female 51KOs and wild type littermates were subjected to various behavioural tests, including the open field, elevated plus maze and forced swim test. The neuroendocrine profile was investigated under basal conditions and in response to an acute stressor. Furthermore, we analysed the mRNA expression levels of the glucocorticoid receptor and corticotrophin release hormone in different brain regions. Overall, female 51KO mice did not display any overt behavioural phenotype under basal conditions, but showed a reduced basal hypothalamic–pituitary–adrenal axis activity, a blunted response to, and an enhanced recovery from, acute stress. These characteristics strongly overlap with previous studies in male 51KO mice indicating that FKBP51 shapes the behavioural and neuroendocrine phenotype

  3. Selective contributions of the medial preoptic nucleus to testosterone-dependant regulation of the paraventricular nucleus of the hypothalamus and the HPA axis.

    PubMed

    Williamson, Martin; Viau, Victor

    2008-10-01

    Previous data have consistently demonstrated an inhibitory effect of androgens on stress-induced hypothalamic-pituitary-adrenal (HPA) responses. Several brain regions may influence androgen-mediated inhibition of the HPA axis, including the medial preoptic area. To test the role of the medial preoptic nucleus (MPN) specifically, we examined in high- and low-testosterone-replaced gonadectomized rats bearing discrete bilateral lesions of the MPN basal and stress-induced indexes of HPA function, and the relative levels of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA in the amygdala. High testosterone replacement decreased plasma adrenocorticotropin hormone (ACTH) and paraventricular nucleus (PVN) Fos responses to restraint exposure in sham- but not in MPN-lesioned animals. AVP-, but not CRH-immunoreactivity staining in the external zone of the median eminence was increased by testosterone in sham animals, and MPN lesions blocked this increment in AVP. A similar interaction between MPN lesions and testosterone occurred on AVP mRNA levels in the medial nucleus of the amygdala. These findings support an involvement of MPN projections in mediating the AVP response to testosterone in both the medial parvocellular PVN and medial amygdala. We conclude that the MPN forms part of an integral circuit that mediates the central effects of gonadal status on neuroendocrine and central stress responses.

  4. Childhood maltreatment and adult psychopathology: pathways to hypothalamic-pituitary-adrenal axis dysfunction

    PubMed Central

    Mello, Marcelo F.; Faria, Alvaro A.; Mello, Andrea F.; Carpenter, Linda L.; Tyrka, Audrey R.; Price, Lawrence H.

    2015-01-01

    Objective The aim of this paper was to examine the relationship between childhood maltreatment and adult psychopathology, as reflected in hypothalamic-pituitary-adrenal axis dysfunction. Method A selective review of the relevant literature was undertaken in order to identify key and illustrative research findings. Results There is now a substantial body of preclinical and clinical evidence derived from a variety of experimental paradigms showing how early-life stress is related to hypothalamic-pituitary-adrenal axis function and psychological state in adulthood, and how that relationship can be modulated by other factors. Discussion The risk for adult psychopathology and hypothalamic-pituitary-adrenal axis dysfunction is related to a complex interaction among multiple experiential factors, as well as to susceptibility genes that interact with those factors. Although acute hypothalamic-pituitary-adrenal axis responses to stress are generally adaptive, excessive responses can lead to deleterious effects. Early-life stress alters hypothalamic-pituitary-adrenal axis function and behavior, but the pattern of hypothalamic-pituitary-adrenal dysfunction and psychological outcome in adulthood reflect both the characteristics of the stressor and other modifying factors. Conclusion Research to date has identified multiple determinants of the hypothalamic-pituitary-adrenal axis dysfunction seen in adults with a history of childhood maltreatment or other early-life stress. Further work is needed to establish whether hypothalamic-pituitary-adrenal axis abnormalities in this context can be used to develop risk endophenotypes for psychiatric and physical illnesses. PMID:19967199

  5. Hypothalamic-pituitary-adrenal axis activity is not elevated in a songbird (Junco hyemalis) preparing for migration.

    PubMed

    Bauer, Carolyn M; Needham, Katie B; Le, Chuong N; Stewart, Emily C; Graham, Jessica L; Ketterson, Ellen D; Greives, Timothy J

    2016-06-01

    During spring, increasing daylengths stimulate gonadal development in migratory birds. However, late-stage reproductive development is typically postponed until migration has been completed. The hypothalamic-pituitary-adrenal (HPA) axis regulates the secretion of glucocorticoids, which have been associated with pre-migratory hyperphagia and fattening. The HPA-axis is also known to suppress the hypothalamic-pituitary-gonadal (HPG) axis, suggesting the possibility that final transition into the breeding life history stage may be slowed by glucocorticoids. We hypothesized that greater HPA-axis activity in individuals preparing for migration may foster preparation for migration while simultaneously acting as a "brake" on the development of the HPG-axis. To test this hypothesis, we sampled baseline corticosterone (CORT), stress-induced CORT, and negative feedback efficacy of Dark-eyed Juncos (Junco hyemalis) in an overwintering population that included both migratory (J.h. hyemalis) and resident (J.h. carolinensis) individuals. We predicted that compared to residents, migrants would have higher baseline CORT, higher stress-induced CORT, and weaker negative feedback. Juncos were sampled in western Virginia in early March, which was about 2-4wk before migratory departure for migrants and 4-5wk before first clutch initiation for residents. Contrary to our predictions, we found that migrants had lower baseline and stress-induced CORT and similar negative feedback efficacy compared with residents, which suggests that delayed breeding in migrants is influenced by other physiological mechanisms. Our findings also suggest that baseline CORT is not elevated during pre-migratory fattening, as migrants had lower baseline CORT and were fatter than residents.

  6. Central organization of androgen-sensitive pathways to the hypothalamic-pituitary-adrenal axis: implications for individual differences in responses to homeostatic threat and predisposition to disease.

    PubMed

    Williamson, Martin; Bingham, Brenda; Viau, Victor

    2005-12-01

    Despite clear evidence of the potency by which sex steroids operate on the hypothalamic-pituitary-adrenal (HPA) axis and genuine sex differences in disorders related to HPA dysfunction, the biological significance of this remains largely ignored. Stress-induced increases in circulating glucocorticoid levels serve to meet the metabolic demands of homeostatic threat head-on. Thus, the nature of the stress-adrenal axis is to protect the organism. As one develops, matures, and ages, still newer and competing physiological and environmental demands are encountered. These changing constraints are also met by shifts in sex steroid release, placing this class of steroids beyond the traditional realm of reproductive function. Here we focus on the dose-related and glucocorticoid-interactive nature by which testosterone operates on stress-induced HPA activation. This provides an overview on how to exploit these characteristics towards developing an anatomical framework of testosterone's actions in the brain, and expands upon the idea that centrally projecting arginine vasopressin circuits in the brain act to register and couple testosterone's effects on neuroendocrine and behavioural responses to stress. More generally, the work presented here underscores how a dual adrenal and gonadal systems approach assist in unmasking the bases by which individuals resist or succumb to stress.

  7. Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus-pituitary-adrenal axis.

    PubMed

    Cai, Li; Li, Rong; Tang, Wen-jian; Meng, Gang; Hu, Xiang-yang; Wu, Ting-ni

    2015-08-01

    Geniposide as the major active component of Gardenia jasminoides Ellis has neuroprotective activity. This study elucidated the potential antidepressant-like effect of geniposide and its related mechanisms using a depression rat model induced by 3 consecutive weeks of chronic unpredictable mild stress (CUMS). Sucrose preference test, open field test (OFT) and forced swimming test (FST) were applied to evaluate the antidepressant effect of geniposide. Adrenocorticotropic hormone (ACTH) and corticosterone (CORT) serum levels, adrenal gland index and hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression were measured to assess the activity of hypothalamus-pituitary-adrenal (HPA) axis. Hypothalamic glucocorticoid receptor α (GRα) mRNA expression and GRα protein expression in hypothalamic paraventricular nucleus (PVN) were also determined by real-time PCR and immunohistochemistry, respectively. We found that geniposide (25, 50, 100mg/kg) treatment reversed the CUMS-induced behavioral abnormalities, as suggested by increased sucrose intake, improved crossing and rearing behavior in OFT, shortened immobility and prolonged swimming time in FST. Additionally, geniposide treatment normalized the CUMS-induced hyperactivity of HPA axis, as evidenced by reduced CORT serum level, adrenal gland index and hypothalamic CRH mRNA expression, with no significant effect on ACTH serum level. Moreover, geniposide treatment upregulated the hypothalamic GRα mRNA level and GRα protein expression in PVN, suggesting geniposide could recover the impaired GRα negative feedback on CRH expression and HPA axis. These aforementioned therapeutic effects of geniposide were essentially similar to fluoxetine. Our results indicated that geniposide possessed potent antidepressant-like properties that may be mediated by its effects on the HPA axis. PMID:25914157

  8. Future Directions in the Study of Social Relationships as Regulators of the HPA Axis across Development

    PubMed Central

    Hostinar, Camelia E.; Gunnar, Megan R.

    2014-01-01

    Many promising findings support the notion that social relationships can dampen HPA axis stress responses and protect individuals from maladaptive psychological and physical disease states. Despite the public health relevance of this topic, little is known about developmental changes in the social regulation of the HPA system, with most prior research having focused on early childhood and adulthood. This gap is particularly striking with regards to adolescence, an age period when it seems likely that reliance on parents as sources of stress-buffering decreases, even as the security of friends and relationship partners as stress buffers may not yet be certain. Furthermore, we speculate that early life stress or abnormal social experiences may impact the propensity to draw mental and physical health benefits from social relationships, but more empirical support for these ideas is needed. Lastly, research linking social support to cumulative life stress has mostly relied on self-report measures of stress, making it difficult to show that social support impacts the type of chronic stress exposure that is associated with increased allostatic load or “wear and tear” on the body and on psychological functioning. Recent advancements in methodology (e.g., assessing hair cortisol levels) as well as composite measures of allostatic load using biomarkers that capture the activity of multiple neuroendocrine, cardiovascular, immune, and metabolic systems will allow us to ask new questions about the extent to which social relationships can impact cumulative life stress and health. PMID:23746193

  9. HPA and SAM axis responses as correlates of self- vs parental ratings of anxiety in boys with an Autistic Disorder.

    PubMed

    Bitsika, Vicki; Sharpley, Christopher F; Sweeney, John A; McFarlane, James R

    2014-03-29

    Anxiety and Autistic Disorder (AD) are both neurological conditions and both disorders share some features that make it difficult to precisely allocate specific symptoms to each disorder. HPA and SAM axis activities have been conclusively associated with anxiety, and may provide a method of validating anxiety rating scale assessments given by parents and their children with AD about those children. Data from HPA axis (salivary cortisol) and SAM axis (salivary alpha amylase) responses were collected from a sample of 32 high-functioning boys (M age=11yr) with an Autistic Disorder (AD) and were compared with the boys' and their mothers' ratings of the boys' anxiety. There was a significant difference between the self-ratings given by the boys and ratings given about them by their mothers. Further, only the boys' self-ratings of their anxiety significantly predicted the HPA axis responses and neither were significantly related to SAM axis responses. Some boys showed cortisol responses which were similar to that previously reported in children who had suffered chronic and severe anxiety arising from stressful social interactions. As well as suggesting that some boys with an AD can provide valid self-assessments of their anxiety, these data also point to the presence of very high levels of chronic HPA-axis arousal and consequent chronic anxiety in these boys.

  10. The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.

    PubMed

    Batalha, Vânia L; Ferreira, Diana G; Coelho, Joana E; Valadas, Jorge S; Gomes, Rui; Temido-Ferreira, Mariana; Shmidt, Tatiana; Baqi, Younis; Buée, Luc; Müller, Christa E; Hamdane, Malika; Outeiro, Tiago F; Bader, Michael; Meijsing, Sebastiaan H; Sadri-Vakili, Ghazaleh; Blum, David; Lopes, Luísa V

    2016-01-01

    Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age-related cognitive impairments may rely on its ability to modulate GR actions.

  11. The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.

    PubMed

    Batalha, Vânia L; Ferreira, Diana G; Coelho, Joana E; Valadas, Jorge S; Gomes, Rui; Temido-Ferreira, Mariana; Shmidt, Tatiana; Baqi, Younis; Buée, Luc; Müller, Christa E; Hamdane, Malika; Outeiro, Tiago F; Bader, Michael; Meijsing, Sebastiaan H; Sadri-Vakili, Ghazaleh; Blum, David; Lopes, Luísa V

    2016-01-01

    Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer's disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer's and age-related cognitive impairments may rely on its ability to modulate GR actions. PMID:27510168

  12. The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function

    PubMed Central

    Batalha, Vânia L.; Ferreira, Diana G.; Coelho, Joana E.; Valadas, Jorge S.; Gomes, Rui; Temido-Ferreira, Mariana; Shmidt, Tatiana; Baqi, Younis; Buée, Luc; Müller, Christa E.; Hamdane, Malika; Outeiro, Tiago F.; Bader, Michael; Meijsing, Sebastiaan H.; Sadri-Vakili, Ghazaleh; Blum, David; Lopes, Luísa V.

    2016-01-01

    Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer’s disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer’s and age-related cognitive impairments may rely on its ability to modulate GR actions. PMID:27510168

  13. Physiological Basis for the Etiology, Diagnosis, and Treatment of Adrenal Disorders: Cushing’s Syndrome, Adrenal Insufficiency, and Congenital Adrenal Hyperplasia

    PubMed Central

    Raff, Hershel; Sharma, Susmeeta T.; Nieman, Lynnette K.

    2014-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a classic neuroendocrine system. One of the best ways to understand the HPA axis is to appreciate its dynamics in the variety of diseases and syndromes that affect it. Excess glucocorticoid activity can be due to endogenous cortisol overproduction (spontaneous Cushing’s syndrome) or exogenous glucocorticoid therapy (iatrogenic Cushing’s syndrome). Endogenous Cushing’s syndrome can be subdivided into ACTH-dependent and ACTH-independent, the latter of which is usually due to autonomous adrenal overproduction. The former can be due to a pituitary corticotroph tumor (usually benign) or ectopic ACTH production from tumors outside the pituitary; both of these tumor types overexpress the proopiomelanocortin gene. The converse of Cushing’s syndrome is the lack of normal cortisol secretion and is usually due to adrenal destruction (primary adrenal insufficiency) or hypopituitarism (secondary adrenal insufficiency). Secondary adrenal insufficiency can also result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy because of HPA axis suppression and adrenal atrophy. Finally, mutations in the steroidogenic enzymes of the adrenal cortex can lead to congenital adrenal hyperplasia and an increase in precursor steroids, particularly androgens. When present in utero, this can lead to masculinization of a female fetus. An understanding of the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases. Furthermore, understanding the pathophysiology of the HPA axis gives great insight into its normal control. PMID:24715566

  14. Peripheral and central sex steroids have differential effects on the HPA axis of male and female rats.

    PubMed

    McCormick, Cheryl M; Linkroum, William; Sallinen, Bethany J; Miller, Nicholas W

    2002-12-01

    Sex differences in hypothalamic-pituitary-adrenal (HPA) function were examined in gonadectomized male and female rats given equivalent sex hormone replacement regimens either using subcutaneous silastic implants (Experiment 1) or cannula implants in the medial preoptic area (MPOA) (Experiment 2) containing either dihydrotestosterone (DHT), testosterone propionate (TP), estradiol benzoate (EB), or left empty (control). Plasma was obtained before and after 20 min of restraint stress to determine plasma ACTH, corticosterone, and CBG levels as measures of HPA function. Consistent with the literature, androgens decreased, and estrogen increased these measures of HPA function, although peripheral implants were more effective than MPOA implants. Gonadectomy and sex hormone treatment did not eliminate sex differences; overall, females had higher levels than males on measures of HPA function. Analyses of variance (ANOVA) indicated interactions of sex and sex hormone treatment on CBG levels and post-stress corticosterone levels in Expt. 1. The results suggest that sexual dimorphisms influence HPA function even when males and females are given equivalent physiological doses of gonadal steroids, and that the relevant sexual dimorphisms involve both the periphery and the CNS.

  15. Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet.

    PubMed

    Michailidou, Z; Carter, R N; Marshall, E; Sutherland, H G; Brownstein, D G; Owen, E; Cockett, K; Kelly, V; Ramage, L; Al-Dujaili, E A S; Ross, M; Maraki, I; Newton, K; Holmes, M C; Seckl, J R; Morton, N M; Kenyon, C J; Chapman, K E

    2008-11-01

    Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR(betageo/+) mice were generated from embryonic stem (ES) cells with a gene trap integration of a beta-galactosidase-neomycin phosphotransferase (betageo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GR(betageo/+) mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GR(betageo/+) mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GR(betageo/+) mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet. PMID:18697839

  16. Daily and photoperiod variations of hypothalamic-pituitary-adrenal axis responsiveness in Japanese quail selected for short or long tonic immobility.

    PubMed

    Hazard, D; Couty, M; Faure, J M; Guémené, D

    2005-12-01

    The aims of this study were to investigate the existence of a circadian rhythm of basal corticosterone (B) plasma concentrations in male and female Japanese quail lines divergently selected for long (LTI) or short (STI) duration of tonic immobility (TI) and the possible effects of photoperiod length on corticotropic axis reactivity. Significant peaks in B levels were observed throughout the day in 3 out of the 4 groups used in our experiments. However, B levels remained very low for all groups (< 5.0 ng/mL) and there was no consensus between groups. We therefore have no evidence from our results that basal B levels follow a circadian rhythm in adult STI and LTI quail held under a long photoperiod (16L:8D). We also showed that rearing under a long photoperiod (16L:8D) was associated with higher basal B levels and higher B adrenal response capacity to 1-24 adrenocorticotropic hormone (ACTH) injection in the STI and LTI lines compared with a shorter period (8L:16D). Higher hypothalamic-pituitary-adrenal (HPA) axis responsiveness to restraint in a crush cage was also measured in female quail reared under the long photoperiod, and similar responses were measured under both photoperiods in males. This result suggests that the effects of photoperiod length involve both local and more central mechanisms in the control of HPA axis responsiveness according to sex. On the other hand, we showed that the genetic selection program for TI responses induced greater increases in the B level following restraint in STI quail than in LTI quail of both sexes under both photoperiods, but the B adrenal response capacity was similar for both lines and sexes. Although further investigations on both lines regarding adrenal sensitivity are necessary before being able to conclude definitively, our findings strongly suggest that the differences observed in HPA axis responsiveness to restraint between lines are probably not due to differences in adrenal function itself but may involve upstream

  17. Stress Sensitivity in Metastatic Breast Cancer: Analysis of Hypothalamic-Pituitary-Adrenal Axis Function

    PubMed Central

    Spiegel, David; Giese-Davis, Janine; Taylor, C. Barr; Kraemer, Helena

    2006-01-01

    The normal diurnal cortisol cycle has a peak in the morning, decreasing rapidly over the day, with low levels during the night, then rising rapidly again to the morning peak. A pattern of flatter daytime slopes has been associated with more rapid cancer progression in both animals and humans. We studied the relationship between the daytime slopes and other daytime cortisol responses to both pharmacological and psychosocial challenges of hypothalamic-pituitary-adrenal (HPA) axis function as well as DHEA in a sample of 99 women with metastatic breast cancer, in hopes of elucidating the dysregulatory process. We found that the different components of HPA regulation: the daytime cortisol slope, the rise in cortisol from waking to 30 minutes later, and cortisol response to various challenges, including dexamethasone (DEX) suppression, corticotrophin releasing factor (CRF) activation, and the Trier Social Stress Task, were at best modestly associated. Escape from suppression stimulated by 1 mg of dexamethasone administered the night before was moderately but significantly associated with flatter daytime cortisol slopes (r=0..28 to .30 at different times of the post dexamethasone administration day, all p<.01) . Daytime cortisol slopes were also moderately but significant associated with the rise in cortisol from waking to 30 minutes after awakening (r=.29, p=.004, N=96), but not with waking cortisol level (r=−0.13, p=.19). However, we could not detect any association between daytime cortisol slope and activation of cortisol secretion by either CRF infusion or the Trier Social Stress Task. The CRF activation test (following 1.5 mg of dexamethasone to assure that the effect was due to exogenous CRF) produced ACTH levels that were correlated (r=0.66 p<.0001, N = 74) with serum cortisol levels, indicating adrenal responsiveness to ACTH stimulation. Daytime cortisol slopes were significantly correlated with the slope of DHEA (r=.21, p=.04, N=95). Our general findings

  18. Hypothalamic-pituitary-adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A.

    PubMed

    Chen, Fang; Zhou, Libin; Bai, Yinyang; Zhou, Rong; Chen, Ling

    2015-05-01

    Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent biological findings in anxiety- and depression-related disorders. The HPA axis is reported to be susceptible to developmental reprogramming. The present study focused on HPA reactivity in postnatal day (PND) 80 male rats exposed perinatally to environmental-dose BPA. When female breeders were orally administered 2 μg/(kg.day) BPA from gestation day 10 to lactation day 7, their offspring (PND 80 BPA-exposed rats) showed obvious anxiety/depression-like behaviors. Notably, significant increase in serum corticosterone and adrenocorticotropin, and corticotropin-releasing hormone mRNA were detected in BPA-exposed rats before or after the mild stressor. Additionally, the level of glucocorticoid receptor mRNA in the hippocampus, but not the hypothalamus, was decreased in BPA-exposed rats. The levels of hippocampal mineralocorticoid receptor mRNA, neuronal nitric oxide synthase and phosphorylated cAMP response element binding protein were increased in BPA-exposed rats. In addition, the testosterone level was in BPA-exposed rats. The results indicate that reprogramming-induced hyperactivity of the HPA axis is an important link between perinatal BPA exposure and persistent potentiation in anxiety and depression. PMID:26060449

  19. HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis.

    PubMed

    Valli, I; Crossley, N A; Day, F; Stone, J; Tognin, S; Mondelli, V; Howes, O; Valmaggia, L; Pariante, C; McGuire, P

    2016-01-01

    The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus-pituitary-adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model.

  20. HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis.

    PubMed

    Valli, I; Crossley, N A; Day, F; Stone, J; Tognin, S; Mondelli, V; Howes, O; Valmaggia, L; Pariante, C; McGuire, P

    2016-01-01

    The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus-pituitary-adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model. PMID:27138796

  1. HPA-axis function and grey matter volume reductions: imaging the diathesis-stress model in individuals at ultra-high risk of psychosis

    PubMed Central

    Valli, I; Crossley, N A; Day, F; Stone, J; Tognin, S; Mondelli, V; Howes, O; Valmaggia, L; Pariante, C; McGuire, P

    2016-01-01

    The onset of psychosis is thought to involve interactions between environmental stressors and the brain, with cortisol as a putative mediator. We examined the relationship between the cortisol stress response and brain structure in subjects at ultra-high risk (UHR) for psychosis. Waking salivary cortisol was measured in 22 individuals at UHR for psychosis and 17 healthy controls. Grey matter volume was assessed using magnetic resonance imaging at 3 T. The relationship between the stress response and grey matter volume was investigated using voxel-based analyses. Our predictions of the topography of cortisol action as a structural brain modulator were informed by measures of brain glucocorticoid and mineralcorticoid receptor distribution obtained from the multimodal neuroanatomical and genetic Allen Brain Atlas. Across all subjects, reduced responsivity of the hypothalamus–pituitary–adrenal (HPA) axis was correlated with smaller grey matter volumes in the frontal, parietal and temporal cortex and in the hippocampus. This relationship was particularly marked in the UHR subjects in the right prefrontal, left parahippocampal/fusiform and parietal cortices. The subgroup that subsequently developed psychosis showed a significant blunting of HPA stress response, observed at trend level also in the whole UHR sample. Altered responses to stress in people at high risk of psychosis are related to reductions in grey matter volume in areas implicated in the vulnerability to psychotic disorders. These areas may represent the neural components of a stress vulnerability model. PMID:27138796

  2. Psychobiological Mechanisms Underlying the Social Buffering of the HPA Axis: A Review of Animal Models and Human Studies across Development

    PubMed Central

    Hostinar, Camelia E.; Sullivan, Regina M.; Gunnar, Megan R.

    2013-01-01

    Discovering the stress-buffering effects of social relationships has been one of the major findings in psychobiology in the last century. However, an understanding of the underlying neurobiological and psychological mechanisms of this buffering is only beginning to emerge. An important avenue of this research concerns the neurocircuitry that can regulate the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis. The present review is a translational effort aimed at integrating animal models and human studies of the social regulation of the HPA axis from infancy to adulthood, specifically focusing on the process that has been named social buffering. This process has been noted across species and consists of a dampened HPA axis stress response to threat or challenge that occurs with the presence or assistance of a conspecific. We describe aspects of the relevant underlying neurobiology when enough information exists and expose major gaps in our understanding across all domains of the literatures we aimed to integrate. We provide a working conceptual model focused on the role of oxytocinergic systems and prefrontal neural networks as two of the putative biological mediators of this process, and propose that the role of early experiences is critical in shaping later social buffering effects. This synthesis points to both general future directions and specific experiments that need to be conducted to build a more comprehensive model of the HPA social buffering effect across the lifespan that incorporates multiple levels of analysis: neuroendocrine, behavioral, and social. PMID:23607429

  3. Reversible Inactivation of the Auditory Thalamus Disrupts HPA Axis Habituation to Repeated Loud Noise Stress Exposures

    PubMed Central

    Day, Heidi E.W.; Masini, Cher V.; Campeau, Serge

    2009-01-01

    Although habituation to stress is a widely observed adaptive mechanism in response to repeated homotypic challenge exposure, its brain location and mechanism of plasticity remains elusive. And while habituation-related plasticity has been suggested to take place in central limbic regions, recent evidence suggests that sensory sites may provide the underlying substrate for this function. For instance, several brainstem, midbrain, thalamic, and/or cortical auditory processing areas, among others, could support habituation-related plasticity to repeated loud noise exposures. In the present study, the auditory thalamus was tested for its putative role in habituation to repeated loud noise exposures, in rats. The auditory thalamus was inactivated reversibly by muscimol injections during repeated loud noise exposures to determine if brainstem or midbrain auditory nuclei would be sufficient to support habituation to this specific stressor, as measured during an additional and drug-free loud noise exposure test. Our results indicate that auditory thalamic inactivation by muscimol disrupts acute HPA axis response specifically to loud noise. Importantly, habituation to repeated loud noise exposures was also prevented by reversible auditory thalamic inactivation, suggesting that this form of plasticity is likely mediated at, or in targets of, the auditory thalamus. PMID:19379718

  4. Stress and Drug Dependence Differentially Modulate Norepinephrine Signaling in Animals with Varied HPA Axis Function

    PubMed Central

    Fox, Megan E; Studebaker, R Isaac; Swofford, Nathaniel J; Wightman, R Mark

    2015-01-01

    Previous work has demonstrated the importance of genetic factors and stress-sensitive circuits in the development of affective disorders. Anxiety and numerous psychological disorders are comorbid with substance abuse, and noradrenergic signaling in the bed nucleus of the stria terminalis (BNST) is thought to be a source of this convergence. Here, we examined the effects of different stressors on behavior and norepinephrine dynamics in the BNST of rat strains known to differ in their HPA-axis function. We compared the effects of acute morphine dependence and social isolation in non-anxious Sprague Dawley (SD) rats, and a depression model, Wistar-Kyoto (WKY) rats. We found a shared phenotype in drug-dependent and singly housed SD rats, characterized by slowed norepinephrine clearance, decreased autoreceptor function, and elevated anxiety. WKY rats exhibited changes in anxiety and autoreceptor function only following morphine dependence. To ascertain the influence of LC inhibition on this plasticity, we administered the LC-terminal-selective toxin DSP-4 to SD and WKY rats. DSP-4-treated SD rats demonstrated a dependence-like phenotype, whereas WKY rats were unchanged. Overall, our findings suggest that individuals with varying stress susceptibilities have different noradrenergic signaling changes in response to stress. These changes may establish conditions that favor stress-induced reinstatement and increase the risk for addiction. PMID:25601230

  5. Mechanisms underlying the effects of prenatal psychosocial stress on child outcomes: beyond the HPA axis.

    PubMed

    Beijers, Roseriet; Buitelaar, Jan K; de Weerth, Carolina

    2014-10-01

    Accumulating evidence from preclinical and clinical studies indicates that maternal psychosocial stress and anxiety during pregnancy adversely affect child outcomes. However, knowledge on the possible mechanisms underlying these relations is limited. In the present paper, we review the most often proposed mechanism, namely that involving the HPA axis and cortisol, as well as other less well-studied but possibly relevant and complementary mechanisms. We present evidence for a role of the following mechanisms: compromised placental functioning, including the 11β-HSD2 enzyme, increased catecholamines, compromised maternal immune system and intestinal microbiota, and altered health behaviors including eating, sleep, and exercise. The roles of (epi)genetics, the postnatal environment and the fetus are also discussed. We conclude that maternal prenatal psychosocial stress is a complex phenomenon that affects maternal emotions, behavior and physiology in many ways, and may influence the physiology and functioning of the fetus through a network of different pathways. The review concludes with recommendations for future research that helps our understanding of the mechanisms by which maternal prenatal stress exerts its effect on the fetus.

  6. Maternal corticosterone effects on hypothalamus-pituitary-adrenal axis regulation and behavior of the offspring in rodents.

    PubMed

    Catalani, Assia; Alemà, Giovanni Sebastiano; Cinque, Carlo; Zuena, Anna Rita; Casolini, Paola

    2011-06-01

    The behavioral and physiological traits of an individual are strongly influenced by early life events. One of the major systems implicated in the responses to environmental manipulations and stress is the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoid hormones (cortisol in humans and corticosterone in rodents) represent the final step in the activation of the HPA system and play an important role in the effects induced by the perinatal environment. We demonstrated, in rats with some differences between males and females, that mothers whose drinking water was supplemented with moderate doses of corticosterone throughout the lactation period, give birth to offspring better able to meet the demands of the environment. The progeny of these mothers, as adults, show improved learning capabilities, reduced fearfulness in anxiogenic situations, lower metabotropic glutamate receptors and higher glucocorticoid receptors in the hippocampus with a persistent hyporeactivity of the HPA axis leading to a resistance to ischemic neuronal damage. Other studies performed in mice showed that low doses of corticosterone in the maternal drinking water, which, as in our rat model, may reflect a form of mild environmental stimulation, enhanced the offspring's ability to cope with different situations, while elevated doses, comparable to those elicited by strong stressors, caused developmental disruption. Significantly, adult rats and mice that had been nursed by mothers with a mild hypercorticosteronemia provide an example of how a moderate corticosterone increase mediates the salutary effects of some events occurring early in life. Both maternal and infantile plasma levels of the hormone may play a role in these effects, the first influencing maternal behavior, the second acting directly on the central nervous system of the developing rat.

  7. Stress, the HPA axis, and nonhuman primate well-being: A review

    PubMed Central

    Novak, Melinda A.; Hamel, Amanda F.; Kelly, Brian J.; Dettmer, Amanda M.; Meyer, Jerrold S.

    2012-01-01

    Numerous stressors are routinely encountered by wild-living primates (e.g., food scarcity, predation, aggressive interactions, and parasitism). Although many of these stressors are eliminated in laboratory environments, other stressors may be present in that access to space and social partners is often restricted. Stress affects many physiological systems including the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the focus of this review. The glucocorticoid, cortisol, is the ultimate output of this system in nonhuman primates, and levels of this hormone are used as an index of stress. Researchers can measure cortisol from several sampling matrices that include blood, saliva, urine, faeces, and hair. A comparison of the advantages and disadvantages of each sampling matrix is provided to aid researchers in selecting an optimal strategy for their research. Stress and its relationship to welfare have been examined in nonhuman primates using two complimentary approaches: comparing baseline cortisol levels under different conditions, or determining the reactivity of the system through exposure to a stressor. Much of this work is focused on colony management practices and developmental models of abnormal behaviour. Certain colony practices are known to increase stress at least temporarily. Both blood sampling and relocation are examples of this effect, and efforts have been made to reduce some of the more stressful aspects of these procedures. In contrast, other colony management practices such as social housing and environmental enrichment are hypothesized to reduce stress. Testing this hypothesis by comparing baseline cortisol levels has not proved useful, probably due to “floor” effects; however, social buffering studies have shown the powerful role of social housing in mitigating reactions of nonhuman primates to stressful events. Models of abnormal behaviour come from two sources: experimentally induced alterations in early experience (e.g., nursery

  8. Influence of early life stress on later hypothalamic–pituitary–adrenal axis functioning and its covariation with mental health symptoms: A study of the allostatic process from childhood into adolescence

    PubMed Central

    Essex, Marilyn J.; Shirtcliff, Elizabeth A.; Burk, Linnea R.; Ruttle, Paula L.; Klein, Marjorie H.; Slattery, Marcia J.; Kalin, Ned H.; Armstrong, Jeffrey M.

    2012-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis is a primary mechanism in the allostatic process through which early life stress (ELS) contributes to disease. Studies of the influence of ELS on children’s HPA axis functioning have yielded inconsistent findings. To address this issue, the present study considers multiple types of ELS (maternal depression, paternal depression, and family expressed anger), mental health symptoms, and two components of HPA functioning (trait-like and epoch-specific activity) in a long-term prospective community study of 357 children. ELS was assessed during the infancy and preschool periods; mental health symptoms and cortisol were assessed at child ages 9, 11, 13, and 15 years. A 3-level hierarchical linear model addressed questions regarding the influences of ELS on HPA functioning and its co-variation with mental health symptoms. ELS influenced trait-like cortisol level and slope, with both hyper- and hypo-arousal evident depending on type of ELS. Further, type(s) of ELS influenced co-variation of epoch-specific HPA functioning and mental health symptoms, with a tighter coupling of HPA alterations with symptom severity among children exposed previously to ELS. Results highlight the importance of examining multiple types of ELS and dynamic HPA functioning in order to capture the allostatic process unfolding across the transition into adolescence. PMID:22018080

  9. Identification of stimulatory and inhibitory inputs to the hypothalamic-pituitary-adrenal axis during hypoglycaemia or transport in ewes.

    PubMed

    Smith, R F; French, N P; Saphier, P W; Lowry, P J; Veldhuis, J D; Dobson, H

    2003-06-01

    This study used the novel approach of statistical modelling to investigate the control of hypothalamic-pituitary-adrenal (HPA) axis and quantify temporal relationships between hormones. Two experimental paradigms were chosen, insulin-induced hypoglycaemia and 2 h transport, to assess differences in control between noncognitive and cognitive stimuli. Vasopressin and corticotropin-releasing hormone (CRH) were measured in hypophysial portal plasma, and adrenocorticotropin hormone (ACTH) and cortisol in jugular plasma of conscious sheep, and deconvolution analysis was used to calculate secretory rates, before modelling. During hypoglycaemia, the relationship between plasma glucose and vasopressin or CRH was best described by log10 transforming variables (i.e. a positive power-curve relationship). A negative-feedback relationship with log10 cortisol concentration 2 h previously was detected. Analysis of the "transport" stimulus suggested that the strength of the perceived stimulus decreased over time after accounting for cortisol facilitation and negative-feedback. The time course of vasopressin and CRH responses to each stimulus were different However, at the pituitary level, the data suggested that log10 ACTH secretion rate was related to log10 vasopressin and CRH concentrations with very similar regression coefficients and an identical ratio of actions (2.3 : 1) for both stimuli. Similar magnitude negative-feedback effects of log10 cortisol at -110 min (hypoglycaemia) or -40 min (transport) were detected, and both models contained a stimulatory relationship with cortisol at 0 min (facilitation). At adrenal gland level, cortisol secretory rates were related to simultaneously measured untransformed ACTH concentration but the regression coefficient for the hypoglycaemia model was 2.5-fold greater than for transport. No individual sustained maximum cortisol secretion for longer than 20 min during hypoglycaemia and 40 min during transport. These unique models demonstrate

  10. Evidence against a critical role of CB1 receptors in adaptation of the hypothalamic-pituitary-adrenal axis and other consequences of daily repeated stress.

    PubMed

    Rabasa, Cristina; Pastor-Ciurana, Jordi; Delgado-Morales, Raúl; Gómez-Román, Almudena; Carrasco, Javier; Gagliano, Humberto; García-Gutiérrez, María S; Manzanares, Jorge; Armario, Antonio

    2015-08-01

    There is evidence that endogenous cannabinoids (eCBs) play a role in the control of the hypothalamic-pituitary-adrenal (HPA) axis, although they appear to have dual, stimulatory and inhibitory, effects. Recent data in rats suggest that eCBs, acting through CB1 receptors (CB1R), may be involved in adaptation of the HPA axis to daily repeated stress. In the present study we analyze this issue in male mice and rats. Using a knock-out mice for the CB1 receptor (CB1-/-) we showed that mutant mice presented similar adrenocorticotropic hormone (ACTH) response to the first IMO as wild-type mice. Daily repeated exposure to 1h of immobilization reduced the ACTH response to the stressor, regardless of the genotype, demonstrating that adaptation occurred to the same extent in absence of CB1R. Prototypical changes observed after repeated stress such as enhanced corticotropin releasing factor (CRH) gene expression in the paraventricular nucleus of the hypothalamus, impaired body weight gain and reduced thymus weight were similarly observed in both genotypes. The lack of effect of CB1R in the expression of HPA adaptation to another similar stressor (restraint) was confirmed in wild-type CD1 mice by the lack of effect of the CB1R antagonist AM251 just before the last exposure to stress. Finally, the latter drug did not blunt the HPA, glucose and behavioral adaptation to daily repeated forced swim in rats. Thus, the present results indicate that CB1R is not critical for overall effects of daily repeated stress or proper adaptation of the HPA axis in mice and rats.

  11. Sensitivity to stress-induced reproductive dysfunction is associated with a selective but not a generalized increase in activity of the adrenal axis.

    PubMed

    Herod, S M; Dettmer, A M; Novak, M A; Meyer, J S; Cameron, J L

    2011-01-01

    Stress-induced reproductive dysfunction is a relatively common cause of infertility in women. In response to everyday life stress, some individuals readily develop reproductive dysfunction (i.e., they are stress sensitive), whereas others are more stress resilient. Female cynomolgus monkeys, when exposed to mild combined psychosocial and metabolic stress (change in social environment + 20% reduced calorie diet), can be categorized as stress sensitive (SS; they rapidly become anovulatory in response to stress), medium stress resilient (MSR; they slowly become anovulatory in response to prolonged stress), or highly stress resilient (HSR; they maintain normal menstrual cycles in response to stress). In this study, we examined whether increased sensitivity to stress-induced reproductive dysfunction is associated with elevated adrenal axis activity by measuring 1) the diurnal release of ACTH and cortisol, 2) ACTH and cortisol in response to an acute psychological stress, 3) the percent suppression of cortisol in response to dexamethasone negative feedback, 4) the diurnal release of ACTH and cortisol following exposure to mild psychosocial and metabolic stress, 5) the concentration of cortisol in hair, and 6) adrenal weight. SS monkeys (n = 5) did not differ from MSR (n = 5) or HSR (n = 7) monkeys in any measurement of baseline HPA axis activity or the integrated measurements of chronic HPA axis activity. However, MSR + SS monkeys (n = 10) did secrete more cortisol than HSR monkeys during the daytime hours (1000-1800) following exposure to a novel social environment and reduced diet. We conclude that increased activity of the HPA axis is unlikely to be the primary mechanism causing increased sensitivity to stress-induced reproductive dysfunction.

  12. Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender.

    PubMed

    Koehl, M; Darnaudéry, M; Dulluc, J; Van Reeth, O; Le Moal, M; Maccari, S

    1999-09-01

    Prenatal stress impairs activity of the hypothalamo-pituitary-adrenal (HPA) axis in response to stress in adult offspring. So far, very few data are available on the effects of prenatal stress on circadian functioning of the HPA axis. Here, we studied the effects of prenatal stress on the circadian rhythm of corticosterone secretion in male and female adult rats. To evaluate the effects of prenatal stress on various regulatory components of corticosterone secretion, we also assessed the diurnal fluctuation of adrenocorticotropin, total and free corticosterone levels, and hippocampal corticosteroid receptors. Finally, in the search of possible maternal factors, we studied the effects of repeated restraint stress on the pattern of corticosterone secretion in pregnant female rats. Results demonstrate that prenatal stress induced higher levels of total and free corticosterone secretion at the end of the light period in both males and females, and hypercorticism over the entire diurnal cycle in females. No diurnal fluctuation of adrenocorticotropin was observed in any group studied. The effects of prenatal stress on corticosterone secretion could be mediated, at least in part, by a reduction in corticosteroid receptors at specific times of day. Results also show that prepartal stress alters the pattern of corticosterone secretion in pregnant females. Those data indicate that prenatally stressed rats exhibit an altered temporal functioning of the HPA axis, which, taken together with their abnormal response to stress, reinforces the idea of a general homeostatic dysfunction in those animals. PMID:10440731

  13. Post weaning high fat feeding affects rats' behavior and hypothalamic pituitary adrenal axis at the onset of puberty in a sexually dimorphic manner.

    PubMed

    Boukouvalas, G; Antoniou, K; Papalexi, E; Kitraki, E

    2008-05-01

    Feeding adult rats with high fat (HF) diets can alter their hypothalamic pituitary adrenal (HPA) axis responsiveness. In the present study, we examined the effect of a high fat diet, applied in rats from weaning to puberty, on their behavior and HPA axis status at puberty onset. Wistar rats of both sexes were fed postweaning with two diets containing either 24% fat (high fat, HF) or 4.3% fat (normal chow) by weight. HF enhanced puberty onset in female rats, without increasing body weight gain in either sex, compared with chow-fed animals. In the forced swim test, HF males exhibited a more active behavioral response on the first day, whereas HF females a more passive response during the second day of the test, as compared with their chow-fed counterparts. In the open field test, HF females showed increased sniffing but reduced rearing, compared with chow-fed females and were less explorative than HF males in the central arena. All animals could learn and recall a water maze task though HF males spent more time in the opposite quadrant than chow-fed males during memory test. The HPA axis status of these animals was investigated under basal conditions. Pubertal fat-fed males had lighter adrenals, while females heavier ones, compared with their counterparts. In addition, plasma corticosterone levels of female rats were increased and glucocorticoid receptor levels in their hypothalamus were reduced due to fat diet, while in males no such changes were detected. We conclude that HF feeding during the prepubertal period can affect behavior and the HPA axis of rats at puberty onset, well before the appearance of the obese state, in a sexually dimorphic manner. Fat diet impacted more the female HPA axis, suggesting that their system is more sensitive to fat-induced nutritional imbalance during adolescence. Present data suggest that the fat-induced nutritional imbalance in young females may lead to neuroendocrine dysfunction that in turn may trigger the appearance of stress

  14. Folliculo-stellate cells - potential mediators of the inflammaging-induced hyperactivity of the hypothalamic-pituitary-adrenal axis in healthy elderly individuals.

    PubMed

    Jovanović, Ivan; Ugrenović, Slađana; Ljubomirović, Miljana; Vasović, Ljiljana; Cukuranović, Rade; Stefanović, Vladisav

    2014-10-01

    Some evidence has suggested that, with age, the hypothalamic-pituitary-adrenal (HPA) axis becomes less resilient, leading to higher glucocorticoids nocturnal levels and a flattening of the circadian profiles. Such age-related changes in the activity of the HPA axis has overexposed the brain and peripheral organs to the effects of the glucocorticoids, increasing the morbidity and mortality rates of the elderly. Debate among scientists regarding the contributions of HPA axis age-related changes of impaired feedback regulation vs. direct overactivation persists. Supporters of impaired feedback regulation assumed that this effect might be the consequence of the hippocampal age-related neuronal loss and the reduction of the number of mineralocorticoid and glucocorticoid receptors. On the other hand, healthy elderly individuals are characterized by an increase of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, and the development of a chronic low-grade inflammatory state, known as inflammaging. Cytokines central to inflammaging send signals to the brain, activate HPA axis, and, by increased cortisol secretion, down-regulate inflammaging in a process known as anti-inflammaging. Even as these cytokines act at the level of the hypothalamic paraventricular nucleus, they are hampered by the intact blood-brain barrier. Further, the corticotropes in the anterior pituitary do not express cytokine receptors, and the density of folliculo-stellate cells generally increases with age. Therefore, we assumed that folliculo-stellate cells were the target structures through which the elevated levels of cytokines, as a part of the inflammaging phenomenon, would cause the overactivation of the HPA axis in healthy elderly individuals. Folliculo-stellate cells are non-endocrine cells that were originally considered to act as supporting cells for the endocrine cells. Despite the fact that FS cells do not produce any of the established hormones of the anterior pituitary, they

  15. Multi-Level Risk Factors for Suicidal Ideation Among at-Risk Adolescent Females: The Role of Hypothalamic-Pituitary-Adrenal Axis Responses to Stress

    PubMed Central

    Calhoun, Casey D.; Hastings, Paul D.; Rudolph, Karen D.; Nock, Matthew K.; Prinstein, Mitchell J.

    2014-01-01

    Adopting a multi-level approach, this study examined risk factors for adolescent suicidal ideation, with specific attention to (a) hypothalamic-pituitary-adrenal (HPA) axis stress responses and (b) the interplay between HPA-axis and other risk factors from multiple domains (i.e., psychological, interpersonal and biological). Participants were 138 adolescent females (Mage=14.13 years, SD=1.40) at risk for suicidal behaviors. At baseline, lifetime suicidal ideation and a number of risk factors were assessed (i.e., depressive symptoms, impulsiveness, pubertal status and peer stress). Participants were exposed to a psychosocial stress task and HPA-axis responses were assessed by measuring cortisol levels pre- and post-stressor. At 3 months post-baseline, suicidal ideation again was assessed. Using group-based trajectory modeling, three groups of cortisol stress-response patterns were identified (i.e., hyporesponsive, normative, and hyperresponsive). As compared to females in the normative and hyporesponsive group, females in the hyperresponsive group were more likely to report a lifetime history of suicidal ideation at baseline, above and beyond the effects of the other predictors. Moreover, as compared to females in the normative group, females in the hyperresponsive group were at increased risk for reporting suicidal ideation 3 months later, after controlling for prior ideation. No interactions between cortisol group and the other risk factors were significant, with the exception of a non-significant trend between impulsiveness and cortisol group on lifetime suicidal ideation. Findings highlight the importance of HPA-axis responses to acute stressors as a risk factor for suicidal ideation among adolescents. PMID:24958308

  16. Impact of maternal undernutrition during the periconceptional period, fetal number, and fetal sex on the development of the hypothalamo-pituitary adrenal axis in sheep during late gestation.

    PubMed

    Edwards, L J; McMillen, I Caroline

    2002-05-01

    Evidence from epidemiologic, clinical, and experimental studies has shown that a suboptimal intrauterine environment during early pregnancy can alter fetal growth and gestation length and is associated with an increased prevalence of adult hypertension and cardiovascular disease. It has been postulated that maternal nutrient restriction may act to reprogram the development of the pituitary-adrenal axis, resulting in excess glucocorticoid exposure and adverse health outcomes in later life. It is unknown, however, whether maternal nutrient restriction during the periconceptional period alters the development of the fetal pituitary-adrenal axis or whether the effects of periconceptional undernutrition can be reversed by the provision of an adequate level of maternal nutrition throughout the remainder of pregnancy. We have investigated the effect of restricted periconceptional nutrition (70% of control feed allowance) from 60 days before until 7 days after mating and the effect of restricted gestational nutrition from Day 8 to 147 of gestation on the development of the fetal hypothalamo-pituitary adrenal (HPA) axis in the sheep. In these studies, we have also investigated the effects of fetal number and sex on the pituitary-adrenal responses to periconceptional and gestational undernutrition. In ewes maintained on a control diet throughout the periconceptional and gestational periods, fetal plasma ACTH concentrations were higher and the prepartum surge in cortisol occurred earlier in singletons compared with twins. Plasma ACTH concentrations were also significantly higher in male compared with female singletons, and in twin fetuses, the prepartum surge in cortisol concentrations occurred earlier in males than in females. Periconceptional undernutrition resulted in higher fetal plasma concentrations of ACTH between 110 and 145 days of gestation and a significantly greater cortisol response to a bolus dose of corticotropin-releasing hormone in twin, but not singleton

  17. Differential changes in the hypothalamic-pituitary-adrenal axis and prolactin responses to stress in early pregnant mice.

    PubMed

    Parker, V J; Menzies, J R W; Douglas, A J

    2011-11-01

    Stress can cause pregnancy failure but it is unclear how the mother's neuroendocrine system responds to stress to impair mechanisms establishing implantation. We analysed stress-evoked hypothalamic-pituitary-adrenal (HPA) axis responses in early pregnant mice. HPA axis secretory responses to immune stress in early-mid pregnancy were strong and similar to that in virgins, although activation of hypothalamic vasopressin neurones, rather than corticotrophin-releasing hormone neurones, may be more important in the stress response in pregnancy. The site and mode of detrimental glucocorticoid action in pregnancy is not established. Because circulating prolactin is important for progesterone secretion and pregnancy establishment, we also hypothesised that stress negatively impacts on prolactin and its neuroendocrine control systems in early pregnant mice. Basal prolactin secretion was profoundly inhibited by either immune or fasting stress in early pregnancy. Prolactin release is inhibited by tonic dopamine release from tuberoinfundibular (TIDA) neurones. However, immune stress did not increase TIDA neurone activity in the median eminence in pregnant mice [measured by 3,4-dihydroxyphenylacetic acid (DOPAC) content and the DOPAC:dopamine ratio]. By contrast, both immune stress and fasting caused weak induction of Fos in TIDA neurones. However, Fos induction does not always reflect dopamine secretion. Taken together, the data suggest that the stress-evoked profound reduction in prolactin secretion does not involve substantially increased dopamine activity as anticipated. In pregnancy, there was also attenuated recruitment of parvocellular paraventricular nucleus neurones and increased activation of brainstem noradrenergic nuclei after immune stress, indicating that other mechanisms may be involved in the suppression of prolactin secretion. In summary, low prolactin and increased circulating glucocorticoids together may partly explain how a mother's endocrine system mediates

  18. Reaction of sleep-wakefulness cycle to stress is related to differences in hypothalamo-pituitary-adrenal axis reactivity in rat.

    PubMed

    Bouyer, J J; Vallée, M; Deminière, J M; Le Moal, M; Mayo, W

    1998-08-31

    Acute stress is known to modify sleep-wakefulness cycle, although with considerable interindividual differences. The origin of these individual differences remains unknown. One possibility is an involvement of the hypothalamo-pituitary-adrenal axis (HPA), as its reactivity is correlated with an individual's behavioral reactivity to stress, and it is known to influence the sleep-wakefulness cycle. The present study was designed to analyze relationships between natural differences in behavioral reactivity to stress associated with differential HPA reactivity and stress-induced changes in sleep-wakefulness. Adult rats were classified into two sub-groups according to their locomotor reactivity to a mild stress (novel environment): the 'low responders (LR)' and the 'high responders (HR)' animals exhibited different glucocorticoid secretion in response to stress. We show that immobilization stress induced an increase in wakefulness in LR animals and a decrease in wakefulness in HR animals. On the other hand, paradoxical sleep was increased in both LR and HR animals. Moreover, we observed that LR animals slept more than the HR animals, whereas the two groups had similar levels of paradoxical sleep. These results indicate that the response of the sleep-wakefulness cycle to stress is related to the behavioral reactivity to stress, in turn governed by the individual's reactivity of the HPA axis. The involvement of dopaminergic mechanisms is discussed. PMID:9729321

  19. Hypothalamic-Ptuitary-Adrenal (HPA) Axis Activity in Adults with Intellectual Disabilities: A Preliminary Investigation

    ERIC Educational Resources Information Center

    Presland, A. D.; Clare, I. C. H.; Broughton, S.; Luke, L.; Wheeler, E.; Fairchild, G.; Watson, P. C.; Chan, W. Y. S.; Kearns, A.; Ring, H. A.

    2013-01-01

    Background: Cortisol is a marker of physiological arousal, exhibiting a characteristic pattern of diurnal activity. The daily cortisol profile has been examined extensively and is atypical in a number of clinical disorders. However, there are very few studies focussing on the cortisol profile in adults with intellectual disabilities (ID). This…

  20. QCM-4, a 5-HT₃ receptor antagonist ameliorates plasma HPA axis hyperactivity, leptin resistance and brain oxidative stress in depression and anxiety-like behavior in obese mice.

    PubMed

    Kurhe, Yeshwant; Mahesh, Radhakrishnan; Devadoss, Thangaraj

    2015-01-01

    Several preclinical studies have revealed antidepressant and anxiolytic-like effect of 5-HT3 receptor antagonists. In our earlier study, we have reported the antidepressive-like effect of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in obese mice subjected to chronic stress. The present study deals with the biochemical mechanisms associated with depression co-morbid with obesity. Mice were fed with high fat diet (HFD) for 14 weeks, further subjected for treatment with QCM-4 (1 and 2mg/kg p.o.) and standard antidepressant escitalopram (ESC) (10mg/kg p.o.) for 28 days. Behavioral assays for depression such as sucrose preference test (SPT), forced swim test (FST) and for anxiety such as light and dark test (LDT) and hole board test (HBT) were performed in obese mice. Biochemical assessments including plasma leptin and corticosterone concentration followed by brain oxidative stress parameters malonaldehyde (MDA) and reduced glutathione (GSH) were performed. Results confirmed that QCM-4 exhibits antidepressive effect by increasing the sucrose consumption in SPT, reducing immobility time in FST and anxiolytic effect by increasing transitions and time in light chamber in LDT, increasing head dip and crossing score in HBT. Furthermore, QCM-4 attenuated the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity by reducing the plasma corticosterone, reversing altered plasma leptin, restoring the imbalance of brain MDA and GSH concentration. In conclusion, QCM-4 showed antidepressive and anxiolytic effect by reversing the behavioral alterations that were supported by biochemical estimations in obese mice.

  1. Maternal early-life trauma and affective parenting style: the mediating role of HPA-axis function.

    PubMed

    Juul, Sarah H; Hendrix, Cassandra; Robinson, Brittany; Stowe, Zachary N; Newport, D Jeffrey; Brennan, Patricia A; Johnson, Katrina C

    2016-02-01

    A history of childhood trauma is associated with increased risk for psychopathology and interpersonal difficulties in adulthood and, for those who have children, impairments in parenting and increased risk of negative outcomes in offspring. Physiological and behavioral mechanisms are poorly understood. In the current study, maternal history of childhood trauma was hypothesized to predict differences in maternal affect and HPA axis functioning. Mother-infant dyads (N = 255) were assessed at 6 months postpartum. Mothers were videotaped during a 3-min naturalistic interaction, and their behavior was coded for positive, neutral, and negative affect. Maternal salivary cortisol was measured six times across the study visit, which also included an infant stressor paradigm. Results showed that childhood trauma history predicted increased neutral affect and decreased mean cortisol in the mothers and that cortisol mediated the association between trauma history and maternal affect. Maternal depression was not associated with affective measures or cortisol. Results suggest that early childhood trauma may disrupt the development of the HPA axis, which in turn impairs affective expression during mother-infant interactions in postpartum women. Interventions aimed at treating psychiatric illness in postpartum women may benefit from specific components to assess and treat trauma-related symptoms and prevent secondary effects on parenting.

  2. Beyond the HPA-axis: The role of the gonadal steroid hormone receptors in modulating stress-related responses in an animal model of PTSD.

    PubMed

    Fenchel, Daphna; Levkovitz, Yechiel; Vainer, Ella; Kaplan, Zeev; Zohar, Joseph; Cohen, Hagit

    2015-06-01

    The hypothalamic-pituitary-adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic-pituitary-gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.

  3. Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse.

    PubMed

    Jiang, Sunny Zhihong; Eiden, Lee E

    2016-07-01

    We measured serum CORT elevation in wild-type and PACAP-deficient C57BL/6N male mice after acute (1 h) or prolonged (2-3 h) daily restraint stress for 7 d. The PACAP dependence of CORT elevation was compared to that of stress-induced hypophagia. Daily restraint induced unhabituated peak CORT elevation, and hypophagia/weight loss, of similar magnitude for 1, 2, and 3 h of daily restraint, in wild-type mice. Peak CORT elevation, and hypophagia, were both attenuated in PACAP-deficient mice for 2 and 3 h daily restraint. Hypophagia induced by 1-h daily restraint was also greatly reduced in PACAP-deficient mice, however CORT elevation, both peak and during recovery from stress, was unaffected. Thus, hypothalamic PACAPergic neurotransmission appears to affect CRH gene transcription and peptide production, but not CRH release, in response to psychogenic stress. A single exposure to restraint sufficed to trigger hypophagia over the following 24 h. PACAP deficiency attenuated HPA axis response (CORT elevation) to prolonged (3 h) but not acute (1 h) single-exposure restraint stress, while hypophagia induced by either a single 1 h or a single 3 h restraint were both abolished in PACAP-deficient mice. These results suggest that PACAP's actions to promote suppression of food intake following an episode of psychogenic stress is unrelated to the release of CRH into the portal circulation to activate the pituitary-adrenal axis. Furthermore, demonstration of suppressed food intake after a single 1-h restraint stress provides a convenient assay for investigating the location of the synapses and circuits mediating the effects of PACAP on the behavioral sequelae of psychogenic stress.

  4. OPRM1 gene variation influences hypothalamic-pituitary-adrenal axis function in response to a variety of stressors in rhesus macaques

    PubMed Central

    Schwandt, Melanie L.; Lindell, Stephen G.; Higley, James D.; Suomi, Stephen J.; Heilig, Markus; Barr, Christina S.

    2011-01-01

    The endogenous opioid system is involved in modulating a number of behavioral and physiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis. In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) is associated with a number of outcomes, including attenuated HPA axis responses to stress. A nonsynonymous variant (OPRM1 C77G) in the rhesus macaque has been shown to have similar effects in vivo to the human variant. The current study investigated whether OPRM1 C77G influences HPA axis response to stress in rhesus macaques. We analyzed plasma adrenocorticotropic hormone (ACTH) and cortisol levels measured in response to three different stressors: 1) maternal separation in infant subjects at 6 months of age, 2) acute ethanol administration in adolescent subjects at 4 years of age, and 3) postpartum HPA axis function in adult rhesus macaque females. For the maternal separation paradigm, ACTH and cortisol levels were determined at baseline as well as peak levels during each of 4 consecutive separation episodes. For the acute ethanol administration paradigm, hormone levels were determined at baseline and again at 5 minutes, 10 minutes, and 60 minutes following the ethanol infusion. For postpartum sampling, hormone levels were determined at postpartum days 7, 14, 21, 30, 60, 90, 120, and 150. Infants carrying the 77G allele exhibited lower levels of cortisol across all 4 separation episodes. Furthermore, adolescents carrying the 77G allele exhibited lower cortisol levels at 5 and 10 minutes following acute ethanol administration. Adult females with prior reproductive experience and who carry the 77G allele exhibited lower cortisol levels across the postpartum period. No significant genotype effects were found for ACTH, although there were some trends for lower ACTH levels in 77G allele carriers. These data are consistent with human studies that have demonstrated attenuated cortisol responses to stress among carriers of the OPRM1 118G allele

  5. Functional sex differences ('sexual diergism') of central nervous system cholinergic systems, vasopressin, and hypothalamic-pituitary-adrenal axis activity in mammals: a selective review.

    PubMed

    Rhodes, M E; Rubin, R T

    1999-08-01

    Sexual dimorphism of the mammalian central nervous system (CNS) has been widely documented. Morphological sex differences in brain areas underlie sex differences in function. To distinguish sex differences in physiological function from underlying sexual dimorphisms, we use the term, sexual diergism, to encompass differences in function between males and females. Whereas the influence of sex hormones on CNS morphological characteristics and function of the hypothalamic-pituitary-gonadal axis has been well-documented, little is known about sexual diergism of CNS control of the hypothalamic-pituitary-adrenal (HPA) axis. Many studies have been conducted on both men and women but have not reported comparisons between them, and many animal studies have used males or females, but not both. From a diergic standpoint, the CNS cholinergic system appears to be more responsive to stress and other stimuli in female than in male mammals; but from a dimorphic standpoint, it is anatomically larger, higher in cell density, and more stable with age in males than in females. Dimorphism often produces diergism, but age, hormones, environment and genetics contribute differentially. This review focuses on the sexual diergism of CNS cholinergic and vasopressinergic systems and their relationship to the HPA axis, with resulting implications for the study of behavior, disease, and therapeutics.

  6. New Directions for the Treatment of Adrenal Insufficiency

    PubMed Central

    Ruiz-Babot, Gerard; Hadjidemetriou, Irene; King, Peter James; Guasti, Leonardo

    2015-01-01

    Adrenal disease, whether primary, caused by defects in the hypothalamic–pituitary–adrenal (HPA) axis, or secondary, caused by defects outside the HPA axis, usually results in adrenal insufficiency, which requires lifelong daily replacement of corticosteroids. However, this kind of therapy is far from ideal as physiological demand for steroids varies considerably throughout the day and increases during periods of stress. The development of alternative curative strategies is therefore needed. In this review, we describe the latest technologies aimed at either isolating or generating de novo cells that could be used for novel, regenerative medicine application in the adrenocortical field. PMID:25999916

  7. Multigenerational effects of fetal dexamethasone exposure on the hypothalamic-pituitary-adrenal axis of first and second generation female offspring

    PubMed Central

    Long, Nathan. M.; Ford, Stephen. P.; Nathanielsz, Peter W.

    2013-01-01

    Objective Synthetic glucocorticoid (sGC) administration to women threatening preterm delivery increases neonatal survival. Evidence shows that fetal exposure to glucocorticoid levels higher than appropriate for current maturation programs offspring development. We examined fetal sGC multigenerational effects on F1 and F2 female offspring hypothalamo-pituitary-adrenal-axis (HPAA) function. Study Design At 0.7 gestation, pregnant F0 ewes received four dexamethasone injections (2mg, approx. 60 ug.kg-1. day-1 12 h apart) or saline (control, C). F1 female offspring were bred to produce F2 female offspring. Post-pubertal HPAA function was tested in F1 and F2 ewes. Results F1 and F2 ewe lambs showed reduced birth-weight and morphometrics. Dexamethasone increased baseline but reduced stimulated HPAA activity in F1 and F2 female offspring. Conclusions This is the first demonstration that sGC doses in the clinical range have multigenerational effects on HPA activity in a precocial species, indicating the need for study of long-term effects of fetal sGC exposure. PMID:23220271

  8. Exercise prevents the increased anxiety-like behavior in lactational di-(2-ethylhexyl) phthalate-exposed female rats in late adolescence by improving the regulation of hypothalamus-pituitary-adrenal axis.

    PubMed

    Wang, Dean-Chuan; Chen, Tsan-Ju; Lin, Ming-Lu; Jhong, Yue-Cih; Chen, Shih-Chieh

    2014-09-01

    Both the detrimental effects of early life adversity and the beneficial effects of exercise on the hypothalamic-pituitary-adrenal (HPA) axis have been reported. Early life exposure to di-(2-ethylhexyl)-phthalate (DEHP) may impair the development of endocrine system. In this study, we investigated the effects of lactational DEHP exposure on stress responses in late adolescent female rats and examined the protective role of treadmill running. Sprague-Dawley dams were fed with DEHP (10mg/kg per day) or vehicle during lactation. After weaning, the female offspring rats were trained to exercise on a treadmill for 5 weeks and then stressed by exploring on an elevated plus maze. The activities of HPA axis were evaluated by measuring the plasma levels of ACTH and corticosterone, the expressions of adrenal enzymes cholesterol side-chain cleavage enzyme (CYP11A1) and cytochrome P-450 11β-hydroxylase (CYP11B1), and the expression of hypothalamic glucocorticoid receptors (GR). The results demonstrate that DEHP-exposed rats exhibited enhanced anxiety-like behaviors. Increased hypothalamic GR and plasma ACTH levels, but decreased adrenal CYP11A1 and corticosterone levels, were observed in DEHP-exposed animals under stressed condition. Importantly, in DEHP-exposed animals, exercise during childhood-adolescence reduced anxiety-like behaviors by normalizing stress-induced alterations in ACTH level and adrenal CYP11A1 expression. The findings of this study suggest that treadmill running may provide beneficial effects on ameliorating the dysregulation of HPA axis in lactational DEHP-exposed adolescent female rats.

  9. Autoimmune diseases of the adrenal glands, parathyroid glands, gonads, and hypothalamic-pituitary axis.

    PubMed

    Muir, A; Maclaren, N K

    1991-09-01

    Autoimmunity directed against the adrenal glands, parathyroid glands, gonads, and hypothalamic-pituitary axis can arise in isolation or as part of a polyglandular autoimmune syndrome. Affected patients can be asymptomatic, but they may also suffer significant morbidity or even mortality. Currently, treatment is restricted largely to hormone replacement when end-organ destruction is almost complete. As our understanding of the pathogenesis of autoimmune endocrinopathies improves, it is probable that early patient detection will become practical and trials of protective immunotherapies entertained.

  10. Alcohol administration attenuates hypothalamic-pituitary-adrenal (HPA) activity in healthy men at low genetic risk for alcoholism, but not in high-risk subjects.

    PubMed

    Mick, Inge; Spring, Konstanze; Uhr, Manfred; Zimmermann, Ulrich S

    2013-09-01

    Acute alcohol challenge studies in rodents and naturalistic observations in drinking alcoholics suggest that alcohol stimulates the hypothalamic-pituitary-adrenal (HPA) system. The literature on respective studies in healthy volunteers is more inconsistent, suggesting differential alcohol effects depending on dosage, recent drinking history, family history of alcoholism and alcohol-induced side effects. These papers and the putative pharmacologic mechanisms underlying alcohol effects on the HPA system are reviewed here and compared with a new study, in which we investigated how secretion of adrenocorticotrophin (ACTH) and cortisol is affected by ingestion of 0.6 g/kg ethanol in 33 young healthy socially drinking males with a paternal history of alcoholism (PHP) versus 30 family history negative (FHN) males. Alcohol and placebo were administered in a 2-day, double-blind, placebo controlled crossover design with randomized administration sequence. After administration of placebo, ACTH and cortisol decreased steadily over 130 minutes. In FHN subjects, secretion of both hormones was even more attenuated after alcohol, resulting in significantly lower levels compared with placebo. In PHP subjects, no alcohol effect on hormone secretion could be detected. The ratio of cortisol to ACTH secretion, each expressed as area under the secretion curve, was significantly increased by alcohol in FHN and PHP participants. These results argue against HPA stimulation being a mechanism that promotes the transition from moderate to dependent drinking. The fact that alcohol-induced HPA suppression was not detected in PHP males is consistent with the general concept that subjects at high risk for alcoholism exhibit less-pronounced alcohol effects.

  11. Stimulatory effect of interleukin-1 beta on the hypothalamic-pituitary-adrenal axis of the rat: influence of age, gender and circulating sex steroids.

    PubMed

    Rivier, C

    1994-03-01

    The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate response of the hypothalamic-pituitary-adrenal (HPA) axis to the stimulatory influence of interleukins (ILs). It is thus reasonable to assume that inappropriate responses of the HPA axis to ILs might play a role in modulating the onset of pathological conditions such as infections. As part of our programme aimed at investigating the ability of ILs to release pro-opiomelanocortin-like peptides and corticosterone in rats exposed to alcohol, we observed that this stimulatory action appeared to be influenced by the gender of the animals. We therefore examined the ability of IL-1 beta, injected peripherally, to stimulate the HPA axis as a function of stage of sexual maturation and the presence or absence of circulating sex steroids. In immature (21 to 22-day-old) rats, both males and females responded to the i.p. administration of 0.5 or 2.0 micrograms IL-1 beta/kg with statistically comparable increases in plasma ACTH levels. In contrast, females released significantly (P < 0.01) more corticosterone in response to the lower dose of cytokine. Forty-day-old intact animals showed no sexual dimorphism in ACTH secretion, but the females again secreted significantly (P < 0.05-0.01) more corticosterone. Gonadectomy, performed 7-8 days prior to the assay, increased the absolute amount of corticosterone released over a 60-min period. A noticeable dimorphism of the ACTH response to IL-1 beta became apparent in 70-day-old intact rats, with females secreting more ACTH than males.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic–pituitary–adrenal axis output in female mice

    PubMed Central

    Pierce, Angela N.; Zhang, Zhen; Fuentes, Isabella M.; Wang, Ruipeng; Ryals, Janelle M.; Christianson, Julie A.

    2015-01-01

    Abstract Experiencing early life stress or injury increases a woman's likelihood of developing vulvodynia and concomitant dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. To investigate the outcome of neonatal vaginal irritation (NVI), female mouse pups were administered intravaginal zymosan on postnatal days 8 and 10 and were assessed as adults for vaginal hypersensitivity by measuring the visceromotor response to vaginal balloon distension (VBD). Western blotting and calcium imaging were performed to measure transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) in the vagina and innervating primary sensory neurons. Serum corticosterone (CORT), mast cell degranulation, and corticotropin-releasing factor receptor 1 (CRF1) expression were measured as indicators of peripheral HPA axis activation. Colorectal and hind paw sensitivity were measured to determine cross-sensitization resulting from NVI. Adult NVI mice had significantly larger visceromotor response during VBD than naive mice. TRPA1 protein expression was significantly elevated in the vagina, and calcium transients evoked by mustard oil (TRPA1 ligand) or capsaicin (TRPV1 ligand) were significantly decreased in dorsal root ganglion from NVI mice, despite displaying increased depolarization-evoked calcium transients. Serum CORT, vaginal mast cell degranulation, and CRF1 protein expression were all significantly increased in NVI mice, as were colorectal and hind paw mechanical and thermal sensitivity. Neonatal treatment with a CRF1 antagonist, NBI 35965, immediately before zymosan administration largely attenuated many of the effects of NVI. These results suggest that NVI produces chronic hypersensitivity of the vagina, as well as of adjacent visceral and distant somatic structures, driven in part by increased HPA axis activation. PMID:26098441

  13. A hypothalamic–pituitary–adrenal axis-associated neuroendocrine metabolic programmed alteration in offspring rats of IUGR induced by prenatal caffeine ingestion

    SciTech Connect

    Xu, D.; Wu, Y.; Liu, F.; Liu, Y.S.; Shen, L.; Lei, Y.Y.; Liu, J.; Ping, J.; Qin, J.; Zhang, C.; Chen, L.B.; Magdalou, J.; Wang, H.

    2012-11-01

    Caffeine is a definite factor of intrauterine growth retardation (IUGR). Previously, we have confirmed that prenatal caffeine ingestion inhibits the development of hypothalamic–pituitary–adrenal (HPA) axis, and alters the glucose and lipid metabolism in IUGR fetal rats. In this study, we aimed to verify a programmed alteration of neuroendocrine metabolism in prenatal caffeine ingested-offspring rats. The results showed that prenatal caffeine (120 mg/kg.day) ingestion caused low body weight and high IUGR rate of pups; the concentrations of blood adrenocorticotropic hormone (ACTH) and corticosterone in caffeine group were significantly increased in the early postnatal period followed by falling in late stage; the level of blood glucose was unchanged, while blood total cholesterol (TCH) and triglyceride (TG) were markedly enhanced in adult. After chronic stress, the concentrations and the gain rates of blood ACTH and corticosterone were obviously increased, meanwhile, the blood glucose increased while the TCH and TG decreased in caffeine group. Further, the hippocampal mineralocorticoid receptor (MR) expression in caffeine group was initially decreased and subsequently increased after birth. After chronic stress, the 11β-hydroxysteroid dehydrogenase-1, glucocorticoid receptor (GR), MR as well as the MR/GR ratio were all significantly decreased. These results suggested that prenatal caffeine ingestion induced the dysfunction of HPA axis and associated neuroendocrine metabolic programmed alteration in IUGR offspring rats, which might be related with the functional injury of hippocampus. These observations provide a valuable experimental basis for explaining the susceptibility of IUGR offspring to metabolic syndrome and associated diseases. -- Highlights: ► Prenatal caffeine ingestion induced HPA axis dysfunction in IUGR offspring rats. ► Caffeine induced a neuroendocrine metabolic programmed alteration in offspring rats. ► Caffeine induced a functional injury

  14. Effect of chronic treatment with the antidepressant tianeptine on the hypothalamo-pituitary-adrenal axis.

    PubMed

    Delbende, C; Tranchand Bunel, D; Tarozzo, G; Grino, M; Oliver, C; Mocaër, E; Vaudry, H

    1994-01-14

    The effects of acute and chronic administration of tianeptine, a novel antidepressant agent, on the hypothalamo-pituitary-adrenal axis were studied in the adult male rat. A single injection of tianeptine did not alter the activity of the hypothalamo-pituitary-adrenal axis. In contrast, chronic administration of tianeptine (10 mg/kg twice a day for 15 days) induced a significant decrease in the concentration of corticotropin-releasing factor (CRF) in the hypothalamus and adrenocorticotropin (ACTH) in the anterior lobe of the pituitary. Chronic tianeptine treatment did not modify CRF levels in the cerebral cortex and hippocampus, and did not alter alpha-melanocyte-stimulating hormone and beta-endorphin levels in the neurointermediate lobe of the pituitary. Using the in situ hybridization technique, we observed that chronic administration of tianeptine did not modify CRF mRNA levels in the paraventricular nucleus of the hypothalamus. The effect of chronic tianeptine treatment on the neuroendocrine response to stress was also investigated. Tube restraint stress for 30 min induced a significant depletion of hypothalamic CRF and a substantial increase of plasma ACTH and corticosterone. Tianeptine abolished the stress-induced reduction of hypothalamic CRF concentration and markedly reduced the stress-induced increase in plasma ACTH and corticosterone levels. Taken together, these results suggest that tianeptine acts primarily at the level of the hypothalamus: (1) in unstressed rats, tianeptine reduces hypothalamic CRF and pituitary ACTH contents; (2) in stressed animals, tianeptine attenuates the activation of the hypothalamo-pituitary-adrenal axis.

  15. Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats.

    PubMed

    Henry, C; Kabbaj, M; Simon, H; Le Moal, M; Maccari, S

    1994-06-01

    Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring. PMID:7920600

  16. [Adrenalitis].

    PubMed

    Saeger, W

    2016-05-01

    Inflammation of the adrenal glands is caused by autoimmunopathies or infections and can induce adrenal insufficiency. Autoimmune lymphocytic adrenalitis is often combined with other autoimmune diseases and the most frequent cause of Addison's disease; however, it only becomes clinically apparent when more than 90 % of the adrenal cortex has been destroyed. Histological features are characterized by lymphoplasmacytic inflammation leading to an increased destruction of adrenocortical tissue but less severe courses can also occur. The second most frequent form of adrenalitis is adrenal tuberculosis, showing typical granulomatous findings that are nearly always caused by spreading from a tuberculous pulmonary focus. Other bacterial as well as viral infections, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and others, generally affect the adrenal glands only in patients with immunodeficiency disorders. In these infections, the adrenal cortex and medulla are frequently involved to roughly the same extent. Although surgical specimens from inflammatory adrenal lesions are extremely rare, the various forms of adrenalitis play an important role in the post-mortem examination of the adrenal glands for clarification of unclear causes of death (e.g. death during an Addisonian crisis). PMID:27099224

  17. The relationship between alcohol consumption, perceived stress, and CRHR1 genotype on the hypothalamic–pituitary–adrenal axis in rural African Americans

    PubMed Central

    Obasi, Ezemenari M.; Shirtcliff, Elizabeth A.; Brody, Gene H.; MacKillop, James; Pittman, Delishia M.; Cavanagh, Lucia; Philibert, Robert A.

    2015-01-01

    Objective: Rurally situated African Americans suffer from stress and drug-related health disparities. Unfortunately, research on potential mechanisms that underlie this public health problem have received limited focus in the scientific literature. This study investigated the effects of perceived stress, alcohol consumption, and genotype on the hypothalamic–pituitary–adrenal (HPA) Axis. Methods: A rural sample of African American emerging adults (n = 84) completed a battery of assessments and provided six samples of salivary cortisol at wakeup, 30 min post wakeup, 90 min post wakeup, 3:00 PM, 3:30 PM, and 4:30 PM. Results: Participants with a TT genotype of the CRHR1 (rs4792887) gene tended to produce the most basal cortisol throughout the day while participants with a CC genotype produced the least amount. Increased levels of perceived stress or alcohol consumption were associated with a blunted cortisol awakening response (CAR). Moreover, the CAR was obliterated for participants who reported both higher stress and alcohol consumption. Conclusion: Perceived stress and alcohol consumption had a deleterious effect on the HPA-Axis. Furthermore, genotype predicted level of cortisol production throughout the day. These findings support the need to further investigate the relationship between stress dysregulation, drug-use vulnerability, and associated health disparities that affect this community. PMID:26150798

  18. Role of Hypothalamic-Pituitary-Adrenal axis and corticotropin-releasing factor stress system on cue-induced relapse to alcohol seeking.

    PubMed

    Galesi, Fernanda L; Ayanwuyi, Lydia O; Mijares, Miriam Garcia; Cippitelli, Andrea; Cannella, Nazzareno; Ciccocioppo, Roberto; Ubaldi, Massimo

    2016-10-01

    A large body of evidence has shown that the Corticotropin Releasing Factor (CRF) system, which plays a key role in stress modulation, is deeply involved in relapse to alcohol seeking induced by exposure to stressful events such as foot shock or yohimbine injections. Exposure to environmental cues is also known to be a trigger for alcohol relapse, nevertheless, the relationship between the relapse evoked by the cue-induced model and the CRF stress systems remains unclear. The purpose of this study was to evaluate, in male Wistar rats, the involvement of the CRF system and Hypothalamic-Pituitary-Adrenal (HPA) axis in relapse induced by environmental cues. Antalarmin, a selective CRF1 receptor antagonist, Metyrapone, a corticosterone (CORT) synthesis inhibitor and CORT were evaluated for their effects on the reinstatement test in a cue-induced relapse model. Antalarmin (20mg/kg) blocked relapse to alcohol seeking induced by environmental cues. Metyrapone (50 and 100mg/kg) also blocked relapse in Wistar rats but only at the highest dose (100mg/kg). Corticosterone had no effect on relapse at the doses tested. The results obtained from this study suggest that the CRF stress system and the HPA axis are involved in cue-induced alcohol relapse. PMID:27316790

  19. Infralimbic cortex controls the activity of the hypothalamus-pituitary-adrenal axis and the formation of aversive memory: Effects of environmental enrichment.

    PubMed

    Ronzoni, Giacomo; Antón, Maria; Mora, Francisco; Segovia, Gregorio; Del Arco, Alberto

    2016-01-15

    The aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABAA antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60 min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone. These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus-pituitary-adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

  20. QCM-4, a 5-HT₃ receptor antagonist ameliorates plasma HPA axis hyperactivity, leptin resistance and brain oxidative stress in depression and anxiety-like behavior in obese mice.

    PubMed

    Kurhe, Yeshwant; Mahesh, Radhakrishnan; Devadoss, Thangaraj

    2015-01-01

    Several preclinical studies have revealed antidepressant and anxiolytic-like effect of 5-HT3 receptor antagonists. In our earlier study, we have reported the antidepressive-like effect of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in obese mice subjected to chronic stress. The present study deals with the biochemical mechanisms associated with depression co-morbid with obesity. Mice were fed with high fat diet (HFD) for 14 weeks, further subjected for treatment with QCM-4 (1 and 2mg/kg p.o.) and standard antidepressant escitalopram (ESC) (10mg/kg p.o.) for 28 days. Behavioral assays for depression such as sucrose preference test (SPT), forced swim test (FST) and for anxiety such as light and dark test (LDT) and hole board test (HBT) were performed in obese mice. Biochemical assessments including plasma leptin and corticosterone concentration followed by brain oxidative stress parameters malonaldehyde (MDA) and reduced glutathione (GSH) were performed. Results confirmed that QCM-4 exhibits antidepressive effect by increasing the sucrose consumption in SPT, reducing immobility time in FST and anxiolytic effect by increasing transitions and time in light chamber in LDT, increasing head dip and crossing score in HBT. Furthermore, QCM-4 attenuated the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity by reducing the plasma corticosterone, reversing altered plasma leptin, restoring the imbalance of brain MDA and GSH concentration. In conclusion, QCM-4 showed antidepressive and anxiolytic effect by reversing the behavioral alterations that were supported by biochemical estimations in obese mice. PMID:25446100

  1. Sex differences in the adult HPA axis and affective behaviors are altered by perinatal exposure to a low dose of bisphenol A.

    PubMed

    Chen, Fang; Zhou, Libin; Bai, Yinyang; Zhou, Rong; Chen, Ling

    2014-07-01

    Bisphenol A (BPA), an estrogen-mimicking endocrine disrupter, when administered perinatally can affect affective behaviors in adult rodents, however the underlying mechanisms remain largely unclear. Postnatal day (PND) 80 vehicle-injected control female rats showed more obvious depression- and anxiety-like behaviors than males, indicative of sexually dimorphic affective behaviors. When female breeders were subcutaneously injected with BPA (2µg/kg) from gestation day 10 to lactation day 7, sex difference of affective behaviors was impaired in their offspring (PND80 BPA-rats), as results that female BPA-rats showed a visible "antianxiety-like" behavior, and male BPA-rats increased depression-like behavior compared to vehicle-injected controls. Notably, basal levels of serum corticosterone and adrenocorticotropin (ACTH), and corticotropin-releasing hormone mRNA were increased in male BPA-rats, but not in female BPA-rats, in comparison with vehicle-injected controls. Following mild-stressor the elevation of corticosterone or ACTH levels was higher in male BPA-rats, whereas it was lower in female BPA-rats than vehicle-injected controls. In comparison with vehicle-injected controls, the level of glucocorticoid receptor (GR) mRNA in hippocampus or hypothalamic paraventricular nucleus was increased in female BPA-rats, while decreased in male BPA-rats. In addition, the levels of hippocampal mineralocorticoid receptor (MR) mRNA, neuronal nitric oxide synthase (nNOS) and phospho-cAMP response element binding protein (p-CREB) were increased in female BPA-rats, but were decreased in male BPA-rats. Furthermore, the testosterone level was reduced in male BPA-rats. The results indicate that the perinatal exposure to BPA through altering the GR and MR expression disrupts the GR-mediated feedback of hypothalamic-pituitary-adrenal (HPA) axis and MR-induced nNOS-CREB signaling, which alters sex difference in affective behaviors. PMID:24857958

  2. Facilitation and feedback in the hypothalamo-pituitary-adrenal axis during food restriction in rats.

    PubMed

    García-Belenguer, S; Oliver, C; Mormède, P

    1993-12-01

    After 4 weeks of food restriction to 50% of ad libitum intake in rats, plasma corticosterone levels were increased, without any change in adrenal weight, and with no evidence of sympathetic nervous system activation (as measured by Tyrosine Hydroxylase and Phenylethanolamine N-Methyl Transferase activities in the adrenal gland). Plasma corticosterone levels were normalized wih the addition of 35% of the calories as sugar. The adrenocortical axis activity was therefore investigated in more detail (nycthemeral cycle of corticosterone levels, ACTH and corticosterone response to a CRF challenge) in ad libitum fed rats and in animals fed 85% or 50% of the intake of the control animals, just before switching the lights off in order to maintain the diurnal rhythm of food intake. Food restriction to 85% did not change mean plasma corticosterone levels but sharpened the peak of corticosterone measured in the evening, indicating that the adrenocortical axis is more sensitive to the endogenous signals responsible for its diurnal cycle of activity. Indeed, the ACTH response to CRF was also increased. A 50% food restriction regimen increased mean corticosterone levels and attenuated the day/night difference, with high corticosterone levels maintained throughout the day. However, the ACTH response to CRF was not different from that measured in ad libitum fed rats, but the corticosterone response was lower, confirming that the adrenal gland is hyposensitive to ACTH. The results are discussed in terms of the balance between inhibiting/activating mechanisms and endocrine/neural influences at each level of the hypothalamo-hypophyso-adrenal axis, depending on the level of food deprivation.

  3. Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli.

    PubMed

    Taylor, S B; Taylor, A R; Markham, J A; Geurts, A M; Kanaskie, B Z; Koenig, J I

    2011-08-01

    Exposure to stress can result in an increased risk for psychiatric disorders, especially among genetically predisposed individuals. Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia and is also associated with psychotic bipolar disorder. In the rat, the neurons of the hypothalamic paraventricular nucleus show strong expression of Nrg1 mRNA. In patients with schizophrenia, a single nucleotide polymorphism in the 5' region of NRG1 interacts with psychosocial stress to affect reactivity to expressed emotion. However, there is virtually no information on the role of NRG1 in hypothalamic-pituitary-adrenal axis function, and whether the protein is expressed in the paraventricular nucleus is unknown. The present studies utilize a unique line of Nrg1 hypomorphic rats (Nrg1(Tn)) generated by gene trapping with the Sleeping Beauty transposon. We first established that the Nrg1(Tn) rats displayed reduced expression of both the mRNA and protein corresponding to the Type II NRG1 isoform. After confirming, using wild type animals, that Type II NRG1 is expressed in the neurocircuitry involved in regulating hypothalamic-pituitary-adrenal axis responses to environmental stimuli, the Nrg1(Tn) rats were then used to test the hypothesis that altered expression of Type II NRG1 disrupts stress regulation and reactivity. In support of this hypothesis, Nrg1(Tn) rats have disrupted basal and acute stress recovery corticosterone secretion, differential changes in expression of glucocorticoid receptors in the pituitary, paraventricular nucleus and hippocampus, and a failure to habituate to an open field. Together, these findings point to NRG1 as a potential novel regulator of neuroendocrine responses to stress as well as behavioral reactivity. PMID:21092742

  4. Sex-specific prenatal stress effects on the rat reproductive axis and adrenal gland structure

    PubMed Central

    George, Susan O; Hogg, Charis O; Lai, Yu-Ting; Brunton, Paula J

    2016-01-01

    Abstract Social stress during pregnancy has profound effects on offspring physiology. This study examined whether an ethologically relevant social stress during late pregnancy in rats alters the reproductive axis and adrenal gland structure in post-pubertal male and female offspring. Prenatally stressed (PNS) pregnant rats (n=9) were exposed to an unfamiliar lactating rat for 10 min/day from day 16 to 20 of pregnancy inclusive, whereas control pregnant rats (n=9) remained in their home cages. Gonads, adrenal glands and blood samples were obtained from one female and one male from each litter at 11 to 12-weeks of age. Anogenital distance was measured. There was no treatment effect on body, adrenal or gonad weight at 11–12 weeks. PNS did not affect the number of primordial, secondary or tertiary ovarian follicles, numbers of corpora lutea or ovarian FSH receptor expression. There was an indication that PNS females had more primary follicles and greater ovarian aromatase expression compared with control females (both P=0.09). PNS males had longer anogenital distances (0.01±0.0 cm/g vs 0.008±0.00 cm/g; P=0.007) and higher plasma FSH concentrations (0.05 ng/mL vs 0.006 ng/mL; s.e.d.=0.023; P=0.043) compared with control males. There were no treatment effects on the number of Sertoli cells or seminiferous tubules, seminiferous tubule area, plasma testosterone concentration or testis expression of aromatase, FSH receptor or androgen receptor. PNS did not affect adrenal size. These data suggest that the developing male reproductive axis is more sensitive to maternal stress and that PNS may enhance aspects of male reproductive development. PMID:27026714

  5. A comparison of two repeated restraint stress paradigms on hypothalamic-pituitary-adrenal axis habituation, gonadal status and central neuropeptide expression in adult male rats.

    PubMed

    Gray, M; Bingham, B; Viau, V

    2010-02-01

    The available evidence continues to illustrate an inhibitory influence of male gonadal activity on the hypothalamic-pituitary-adrenal (HPA) axis under acute stress. However, far less is known about how these systems interact during repeated stress. Because HPA output consistently declines across studies examining repeated restraint, the potential mechanisms mediating this habituation are often inferred as being equivalent, even though these studies use a spectrum of restraint durations and exposures. To test this generalisation, as well as to emphasise a potential influence of the male gonadal axis on the process of HPA habituation, we compared the effects of two commonly used paradigms of repeated restraint in the rodent: ten daily episodes of 0.5 h of restraint and five daily episodes of 3 h of restraint. Both paradigms produced comparable declines in adrenocorticotrophic hormone and corticosterone between the first and last day of testing. However, marked differences in testosterone levels, as well as corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) expression, occurred between the two stress groups. Plasma testosterone levels remained relatively higher in animals exposed to 0.5 h of restraint compared to 3 h of restraint, whereas forebrain gonadotrophin-releasing hormone (GnRH) cell counts increased in both groups. AVP mRNA was increased after 3 h, but not after 0.5 h of repeated restraint, in the medial parvicellular paraventricular nucleus and in the posterior bed nucleus of the stria terminalis (BST), and increased with 0.5 h of repeated restraint in the medial amygdala. CRH mRNA was increased after 3 h, but not after 0.5 h of repeated restraint, in the central amygdala and anterior BST. The data obtained illustrate that, despite comparable declines in HPA responses, the pathways recruited for stress adaptation appear to be distinct between restraint groups. Given the extreme sensitivity of limbic AVP to testosterone, and conversely CRH

  6. Chronic Heroin Dependence Leading to Adrenal Insufficiency

    PubMed Central

    2014-01-01

    Opioids have been the mainstay for pain relief and palliation over a long period of time. They are commonly abused by drug addicts and such dependence usually imparts severe physiologic effects on multiple organ systems. The negative impact of opioids on the endocrine system is poorly understood and often underestimated. We describe a patient who developed severe suppression of the hypothalamic-pituitary adrenal (HPA) axis leading to secondary adrenal insufficiency due to long standing abuse of opioids. PMID:25221675

  7. Hypothalamic-Pituitary-Adrenal Axis Function in Dissociative Disorders, PTSD, and Healthy Volunteers

    PubMed Central

    Simeon, Daphne; Knutelska, Margaret; Yehuda, Rachel; Putnam, Frank; Schmeidler, James; Smith, Lisa M.

    2007-01-01

    Background This study investigated basal and stress-induced HPA axis alterations in dissociative disorders (DD). Methods Forty-six subjects with DD without lifetime PTSD, 35 subjects with PTSD, and 58 HC subjects, free of current major depression, were studied as inpatients. After a 24-hour urine collection and hourly blood sampling for ambient cortisol determination, a low-dose dexamethasone suppression test was administered, followed by the Trier Social Stress Test. Results The DD group had significantly elevated urinary cortisol compared to the HC group, more pronounced in the absence of lifetime major depression, whereas the PTSD and HC groups did not differ. The DD group demonstrated significantly greater resistance to, and faster escape from, dexamethasone suppression compared to the HC group, whereas the PTSD and HC groups did not differ. The three groups did not differ in cortisol stress reactivity, but both psychiatric groups demonstrated a significant inverse correlation between dissociation severity and cortisol reactivity, after controlling for all other symptomatology. The PTSD subgroup with comorbid DD tended to have blunted reactivity compared to the HC group. Conclusions The study demonstrates a distinct pattern of HPA axis dysregulation in DD, emphasizing the importance of further study of stress response systems in dissociative psychopathology. PMID:17137559

  8. Gender difference in hypothalamic-pituitary-adrenal axis response to alcohol in the rat: activational role of gonadal steroids.

    PubMed

    Ogilvie, K M; Rivier, C

    1997-08-22

    Alcohol administration activates the hypothalamic-pituitary-adrenal (HPA) axis of both male and female rats, with females secreting more adrenocorticotropin (ACTH) and corticosterone than males in response to the same dose of alcohol. Our earlier work suggested that this gender difference arises due to the activational effects of gonadal steroids. In particular, we hypothesized that both androgens and estrogens play a role, with androgens exerting an inhibitory influence while estrogens elevate activity of the HPA. In the present studies, we tested this hypothesis by manipulating steroidal milieu in male rats using surgical castration and chronic implantation of testosterone (T), dihydrotestosterone (DHT), or estradiol (E2). Intact male and female rats were included as controls. Injection of alcohol (3 g/kg b.wt., i.p.) resulted in elevation of blood alcohol levels, ACTH and corticosterone in all groups. However, the amount of ACTH secreted was greater in females and castrated males implanted with E2 than in intact males. In castrated males, regardless of androgen implantation, the ACTH response was intermediate, with mean levels between those of females and males, but not differing significantly from either. In contrast to the ACTH results, significantly higher corticosterone secretion was measured in females and castrated males which did not receive a steroid implant. Since there were no significant differences between groups in blood alcohol levels (BALs), these results are not due to steroid-dependent alterations in alcohol metabolism. Because the ACTH data confirmed an activational effect of E2, we sought to determine whether this steroid regulated levels of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) mRNAs in the paraventricular nucleus of the hypothalamus (PVN). Four pretreatment groups were studied: intact males, intact females, castrated males, and castrated males implanted with E2. Two weeks after surgery, alcohol or vehicle was

  9. Hypothalamic-pituitary-adrenal axis activation and immune regulation in heat-stressed sheep after supplementation with polyunsaturated fatty acids.

    PubMed

    Caroprese, M; Ciliberti, M G; Annicchiarico, G; Albenzio, M; Muscio, A; Sevi, A

    2014-07-01

    The aim of this study was to assess the effects of supplementation with polyunsaturated fatty acids from different sources on immune regulation and hypothalamic-pituitary-adrenal (HPA) axis activation in heat-stressed sheep. The experiment was carried out during the summer 2012. Thirty-two Comisana ewes were divided into 4 groups (8 sheep/group): (1) supplemented with whole flaxseed (FS); (2) supplemented with Ascophyllum nodosum (AG); (3) supplemented with a combination of flaxseed and A. nodosum (FS+AG); and (4) control (C; no supplementation). On d 22 of the experiment, cortisol concentrations in sheep blood were measured after an injection of ACTH. Cellular immune response was evaluated by intradermic injection of phytohemagglutinin (PHA) at 0, 15, and 30 d of the trial. Humoral response to ovalbumin (OVA) was measured at 0, 15, and 30 d. At 0, 15, and 30 d of the experiment, blood samples were collected from each ewe to determine production of T-helper (Th)1 cytokines (IL-12 and IFN-γ), and Th2 cytokines (IL-10, IL-4, IL-13), and concentrations of heat shock proteins (HSP) 70 and 90. Ewes supplemented with flaxseed alone had greater cortisol concentrations and a longer-lasting cell-mediated immune response compared with ewes in the control and other groups. Anti-OVA IgG concentrations increased in all groups throughout the trial, even though ewes in the FS+AG group had the lowest anti-OVA IgG concentrations at 15 d. The level of IL-10 increased in all groups throughout the experiment; the FS+AG group had the lowest IL-13 concentration at 15 and 30 d. The concentration of HSP 70 increased in AG ewes at the end of the experiment and decreased in FS ewes, whereas that of HSP 90 increased in FS ewes compared with FS+AG ewes. Flaxseed supplementation was found to influence in vivo HPA activation in heat-stressed sheep, resulting in increased cortisol concentrations, probably to meet increased energy demand for thermoregulation. Flaxseed supplementation also

  10. Investigation of Genetic Variants, Birthweight and Hypothalamic-Pituitary-Adrenal Axis Function Suggests a Genetic Variant in the SERPINA6 Gene Is Associated with Corticosteroid Binding Globulin in the Western Australia Pregnancy Cohort (Raine) Study

    PubMed Central

    Anderson, Laura N.; Briollais, Laurent; Atkinson, Helen C.; Marsh, Julie A.; Xu, Jingxiong; Connor, Kristin L.; Matthews, Stephen G.; Pennell, Craig E.; Lye, Stephen J.

    2014-01-01

    Background The hypothalamic-pituitary-adrenal (HPA) axis regulates stress responses and HPA dysfunction has been associated with several chronic diseases. Low birthweight may be associated with HPA dysfunction in later life, yet human studies are inconclusive. The primary study aim was to identify genetic variants associated with HPA axis function. A secondary aim was to evaluate if these variants modify the association between birthweight and HPA axis function in adolescents. Methods Morning fasted blood samples were collected from children of the Western Australia Pregnancy Cohort (Raine) at age 17 (n = 1077). Basal HPA axis function was assessed by total cortisol, corticosteroid binding globulin (CBG), and adrenocorticotropic hormone (ACTH). The associations between 124 tag single nucleotide polymorphisms (SNPs) within 16 HPA pathway candidate genes and each hormone were evaluated using multivariate linear regression and penalized linear regression analysis using the HyperLasso method. Results The penalized regression analysis revealed one candidate gene SNP, rs11621961 in the CBG encoding gene (SERPINA6), significantly associated with total cortisol and CBG. No other candidate gene SNPs were significant after applying the penalty or adjusting for multiple comparisons; however, several SNPs approached significance. For example, rs907621 (p = 0.002) and rs3846326 (p = 0.003) in the mineralocorticoid receptor gene (NR3C2) were associated with ACTH and SERPINA6 SNPs rs941601 (p = 0.004) and rs11622665 (p = 0.008), were associated with CBG. To further investigate our findings for SERPINA6, rare and common SNPs in the gene were imputed from the 1,000 genomes data and 8 SNPs across the gene were significantly associated with CBG levels after adjustment for multiple comparisons. Birthweight was not associated with any HPA outcome, and none of the gene-birthweight interactions were significant after adjustment for multiple comparisons. Conclusions

  11. Hypothalamic Norepinephrine Mediates Acupunctural Effects on Hypothalamic-Pituitary-Adrenal Axis During Ethanol Withdrawal.

    PubMed

    Zhao, Zheng Lin; Kim, Sang Chan; Zhang, Jie; Liu, Hong Feng; Lee, Bong Hyo; Jang, Eun Young; Lee, Chul Won; Cho, Il Je; An, Won G; Yang, Chae Ha; Kim, Young Woo; Zhao, Rong Jie; Wu, Yi Yan

    2016-02-01

    A previous study demonstrated that acupuncture at ST36 (Zu-San-Li) attenuates ethanol withdrawal (EW)-induced hyperactivation of the hypothalamic-pituitary-adrenal axis in rats. The current study investigated the involvement of hypothalamic norepinephrine (NE) in that process. Rats were intraperitoneally treated with 3 g/kg/d of ethanol or saline for 28 days. After 24 hours of EW, acupuncture was applied to rats at bilateral ST36 points or at nonacupoints (tail) for 1 minute. A high-performance liquid chromatography analysis showed that EW significantly increased both the NE and the 3-methoxy-4-hydroxy-phenylglycol (MHPG) levels in the hypothalamic paraventricular nucleus (PVN). Western blot analysis also revealed that EW markedly elevated the phosphorylation rates of tyrosine hydroxylase (TH), but spared TH protein expression in the PVN. However, acupuncture at ST36, but not at nonacupoints, greatly inhibited the increase in the hypothalamic NE, MHPG, and phosphorylation rates of TH. Additionally, postacupuncture infusion of NE into the PVN significantly attenuated the inhibitory effects of acupuncture at ST36 on the oversecretion of plasma corticosterone during EW. These results suggest that acupuncture at ST36 inhibits EW-induced hyperactivation of the hypothalamic NEergic system to produce therapeutic effects on the hypothalamic-pituitary-adrenal axis.

  12. Stimulation of the hypothalamo-pituitary-adrenal axis in the rat by the type 4 phosphodiesterase (PDE-4) inhibitor, denbufylline.

    PubMed Central

    Hadley, A. J.; Kumari, M.; Cover, P. O.; Osborne, J.; Poyser, R.; Flack, J. D.; Buckingham, J. C.

    1996-01-01

    1. Preliminary studies in our laboratories showed that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally to adult male rats. This paper describes the results of experiments in which well established in vivo and in vitro models were used to (a) examine further the effects of denbufylline on HPA function and (b) identify the site and mode of action of the drug within the axis. 2. In vivo, administration of denbufylline (0.1-2.5 mg kg-1, i.p.) produced a significant increase in the serum corticosterone concentration; maximal responses were attained at a dose of 1.0 mg kg-1 (P < 0.01 vs. vehicle control, Scheffe's test). However, when denbufylline was administered by intracerebroventricular injection (0.05-1 micrograms kg-1) it failed to influence significantly the serum corticosterone concentration (P > 0.05 vs. vehicle control, Scheffe's test). The adrenocortical responses to peripheral injections of denbufylline (1 mg kg-1, i.p.) were reduced in rats in which the secretion of endogenous corticotrophin releasing factors (CRFs) from the hypothalamus was blocked pharmacologically (P < 0.01 vs. controls, Scheffe's test). However, denbufylline (0.1 mg kg-1, i.p.) potentiated the significant (P < 0.01) increases in serum corticosterone concentration provoked in "CRF blocked rats' by hypothalamic extract (5 hypothalamic extracts kg-1, i.v.) although it failed to influence (P > 0.05) the relatively moderate increases in corticosterone secretion evoked by CRH-41 (2 mg kg-1, i.v.). 3. In vitro, denbufylline (0.01-1 mM) evoked small but significant (P < 0.05) increases in the release of ACTH from rat anterior pituitary segments; furthermore, at these and lower concentrations (0.01 microM-1 mM), it potentiated the adrenocorticotrophic responses to sub-maximal concentrations of hypothalamic extract (P < 0.01) and forskolin (0.1 mM, P < 0

  13. Active hypothalamic-pituitary-gonadal axis in an infant with X-linked adrenal hypoplasia congenita.

    PubMed

    Takahashi, T; Shoji, Y; Shoji, Y; Haraguchi, N; Takahashi, I; Takada, G

    1997-03-01

    To evaluate the hypothalamic-pituitary-gonadal axis in an infant with adrenal hypoplasia congenita, we measured the serum levels of testosterone and performed a luteinizing hormone-releasing hormone stimulation test. The diagnosis was made because of the presence of a mutation, A300V, in the DAX-1 gene. The results demonstrated an active hypothalamic-pituitary-gonadal axis, with adult-level testosterone of 266 ng/dl on day 0, and maintenance of testosterone concentration in the 100 to 250 ng/dl range for 140 days as expected. The luteinizing hormone-releasing hormone lest was compatible with an active pituitary gland with a luteinizing hormone peak of 13.1 IU/L and a follicle-stimulating hormone of 5.0 IU/L We conclude that the DAX-1 mutation does allow a normal reproductive axis at birth. We speculate that sometime between infancy and puberty this mutation in the DAX-1 gene leads to an inability to activate the reproductive axis from its childhood suppression; thus puberty will not develop in this infant.

  14. The influence of DHEA pretreatment on prepulse inhibition and the HPA-axis stress response in rat offspring exposed prenatally to polyriboinosinic-polyribocytidylic-acid (PIC).

    PubMed

    Maayan, Rachel; Ram, Edward; Biton, Doron; Cohen, Hagit; Baharav, Ehud; Strous, Rael D; Weizman, Abraham

    2012-07-11

    Prenatal exposure to maternal infection may be associated with the development of neurodevelopmental disorders as well as increased susceptibility to the development of schizophrenia. Prenatal administration of polyriboinosinic-polyribocytidilic-acid, mimicking RNA virus exposure, has been shown to induce schizophrenia-like behavioral, neurochemical and neuorophysiological abnormalities in rodent offspring. In the present study PIC prenatal administration at gestation day 15 was associated with alterations in the acoustic-startle-response/prepulse-inhibition [ASR/PPI] and the HPA-axis stress response in rat offspring on day 90. We show that pretreatment with dehydroepiandrosterone (DHEA) reverses PIC-related ASR/PPI disruption in female rats and normalizes HPA-axis stress response in a united group of male and female rats. Further research in both animal and human studies is recommended in order to confirm these preliminary findings and their application to the understanding and management of schizophrenia and related conditions.

  15. In search of the HPA axis activity in unipolar depression patients with childhood trauma: Combined cortisol awakening response and dexamethasone suppression test.

    PubMed

    Lu, Shaojia; Gao, Weijia; Huang, Manli; Li, Lingjiang; Xu, Yi

    2016-07-01

    The aim of the present study was to examine the impact of childhood trauma on HPA axis activity both in depression patients and healthy controls in order to determine the role of HPA axis abnormalities in depression and to find the differences in HPA axis functioning that may lead certain individuals more susceptible to the depressogenic effects of childhood trauma. Eighty subjects aged 18-45 years were recruited into four study groups (n = 18, depression patients with childhood trauma exposures, CTE/MDD; n = 17, depression patients without childhood adversity, non-CTE/MDD; n = 23, healthy persons with childhood trauma, CTE/non-MDD; and n = 22, healthy persons without childhood adversity, non-CTE/non-MDD). Each participant collected salivary samples in the morning at four time points: immediately upon awakening, 30, 45, and 60 min after awakening for the assessment of CAR and underwent a 1 mg-dexamethasone suppression test (DST). Regardless of depression, subjects with CTE exhibited an enhanced CAR and the CAR areas under the curve to ground (AUCg) were associated with their childhood trauma questionnaire (CTQ) physical neglect scores and CTQ total scores. In addition, the CTE/MDD group also showed a highest post-DST cortisol concentration and a decreased glucocorticoid feedback inhibition among four groups of subjects. The present findings suggested that childhood trauma was associated with hyperactivity of HPA axis as measured with CAR, potentially reflecting the vulnerability for developing depression after early life stress exposures. Moreover, dysfunction of the GR-mediated negative feedback control might contribute to the development of depression after CTE.

  16. In search of the HPA axis activity in unipolar depression patients with childhood trauma: Combined cortisol awakening response and dexamethasone suppression test.

    PubMed

    Lu, Shaojia; Gao, Weijia; Huang, Manli; Li, Lingjiang; Xu, Yi

    2016-07-01

    The aim of the present study was to examine the impact of childhood trauma on HPA axis activity both in depression patients and healthy controls in order to determine the role of HPA axis abnormalities in depression and to find the differences in HPA axis functioning that may lead certain individuals more susceptible to the depressogenic effects of childhood trauma. Eighty subjects aged 18-45 years were recruited into four study groups (n = 18, depression patients with childhood trauma exposures, CTE/MDD; n = 17, depression patients without childhood adversity, non-CTE/MDD; n = 23, healthy persons with childhood trauma, CTE/non-MDD; and n = 22, healthy persons without childhood adversity, non-CTE/non-MDD). Each participant collected salivary samples in the morning at four time points: immediately upon awakening, 30, 45, and 60 min after awakening for the assessment of CAR and underwent a 1 mg-dexamethasone suppression test (DST). Regardless of depression, subjects with CTE exhibited an enhanced CAR and the CAR areas under the curve to ground (AUCg) were associated with their childhood trauma questionnaire (CTQ) physical neglect scores and CTQ total scores. In addition, the CTE/MDD group also showed a highest post-DST cortisol concentration and a decreased glucocorticoid feedback inhibition among four groups of subjects. The present findings suggested that childhood trauma was associated with hyperactivity of HPA axis as measured with CAR, potentially reflecting the vulnerability for developing depression after early life stress exposures. Moreover, dysfunction of the GR-mediated negative feedback control might contribute to the development of depression after CTE. PMID:27049575

  17. The hypothalamic-pituitary-adrenal and the hypothalamic- pituitary-gonadal axes interplay.

    PubMed

    Mastorakos, George; Pavlatou, Maria G; Mizamtsidi, Maria

    2006-01-01

    Vertebrates respond to stress with activation of the hypothalamic-pituitary-adrenal (HPA) axis, the adrenergic and the autonomic nervous systems. The principal central nervous system regulators of the HPA axis are corticotropin releasing hormone (CRH) and antidiuretic hormone (AVP). Apart from in the central nervous system, CRH has been found in the adrenal medulla, ovaries, myometrium, endometrium, placenta, testis and elsewhere. The activation of the HPA axis during stress affects all body systems. The reproductive axis is inhibited by the HPA axis for the sake of saving energy. The changes to the hypothalamic-pituitary-gonadal (HPG) axis during stress are species-specific, and depend on the type and duration of the stimulus. Several conditions may be associated with altered regulation of the HPA axis. Polycystic ovary syndrome, anorexia nervosa and pregnancy in the third trimester are all characterized by HPA axis activation. In contrast, during the postpartum period, HPA axis suppression is implicated in the "postpartum blues". The actions of CRH are also essential in fetal development and neonatal survival.

  18. Corticotropin-releasing hormone and the sympathoadrenal system are major mediators in the effects of peripherally administered exendin-4 on the hypothalamic-pituitary-adrenal axis of male rats.

    PubMed

    Gil-Lozano, Manuel; Romaní-Pérez, Marina; Outeiriño-Iglesias, Verónica; Vigo, Eva; González-Matías, Lucas C; Brubaker, Patricia L; Mallo, Federico

    2014-07-01

    Glucagon-like peptide-1 (GLP-1) and the GLP-1 receptor agonist, exendin-4 (Ex-4), potently stimulate hypothalamic-pituitary-adrenal (HPA) axis activity after either central or peripheral administration. Because several GLP-1 derivative drugs, including synthetic Ex-4, are currently in use to treat patients with type II diabetes mellitus, the characterization of Ex-4 effects on the HPA axis is highly relevant. Herein, the roles of CRH and AVP on these effects were investigated by administering the antagonists astressin and d(CH2)5Tyr(Me)AVP, respectively. The role of the sympathoadrenal system (SAS) was explored in bilateral adrenal enucleated and guanethidine-treated rats, whereas primary pituitary cell cultures were used to study direct effects on the corticotropes. Astressin completely abrogated (P < .05) the effects of Ex-4 central administration on ACTH secretion but only slightly reduced (by 35%) the ACTH response to Ex-4 peripheral administration. Moreover, astressin significantly (P < .05) decreased the corticosterone response to centrally but not peripherally administered Ex-4, suggesting different mechanisms depending on the route of administration. Pretreatment with d(CH2)5Tyr(Me)AVP failed to diminish either the ACTH or corticosterone response to Ex-4 and no direct effect of Ex-4 or GLP-1 was observed on pituitary cell cultures. In contrast, a significant (P < .05) reduction in the corticosterone response elicited by Ex-4 peripheral administration was observed in enucleated and guanethidine-treated rats, indicating a role of the SAS in the glucocorticoid stimulatory effects of Ex-4. Our data demonstrate that the effects of Ex-4 on the HPA axis are partially mediated by CRH and the sympathoadrenal system, and stress the relevance of Ex-4 as a corticosterone secretagogue.

  19. Investigations of HPA Function and the Enduring Consequences of Stressors in Adolescence in Animal Models

    ERIC Educational Resources Information Center

    McCormick, Cheryl M.; Mathews, Iva Z.; Thomas, Catherine; Waters, Patti

    2010-01-01

    Developmental differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to stressors and ongoing development of glucocorticoid-sensitive brain regions in adolescence suggest that similar to the neonatal period of ontogeny, adolescence may also be a sensitive period for programming effects of stressors on the central nervous system.…

  20. Arginine Vasopressin and Arginine Vasopressin Receptor 1b Involved in Electroacupuncture‐Attenuated Hypothalamic‐Pituitary‐Adrenal Axis Hyperactivity in Hepatectomy Rats

    PubMed Central

    Zhu, Jing; Chen, Zhejun; Zhu, LiTing; Meng, ZeHui; Wu, GenCheng

    2015-01-01

    Objective The study aims to know the effect of electroacupuncture (EA) in maintenance of the homeostasis of the neuroendocrine system in hepatectomy rats and the involvement of arginine vasopressin (AVP) signaling in hypothalamus after EA was observed. Materials and Methods Rats were randomly assigned to four groups, including the intact group, model group, sham‐EA group, and EA group. EA was given during the perioperative period at the Zusanli (ST36) and Sanyinjiao (SP6) points after hepatectomy. The serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels were detected via radioimmunoassay. The expression of AVP, arginine vasopressin receptor 1a (AVPR1a), arginine vasopressin receptor 1b (AVPR1b), and glucocorticoid receptor (GR) was detected by Western blot after surgery. Results Compared with the intact group, the ACTH and CORT levels in the serum of model group were increased, whereas the ACTH and CORT levels were decreased in the EA group compared with the model group. Moreover, AVP and AVPR1b protein levels in the pituitary gland were increased in the model group and decreased in the EA group. Further, a distinct increase in the AVP and AVPR1a protein levels was observed in the model group, whereas they were significantly decreased in the EA group. Blockade of AVPR1b by nelivaptan reduced the increase of ACTH and CORT. D [Leu4, Lys8] vasopressin can inhibit the effect of EA in rectification of the hyperactivity of the hypothalamic‐pituitary‐adrenal (HPA) axis. Conclusions EA application at ST36 and SP6 can ameliorate the hyperactivity of the HPA axis via AVP signaling during the perioperative period. PMID:26573696

  1. Embryonic exposure to corticosterone modifies aggressive behavior through alterations of the hypothalamic pituitary adrenal axis and the serotonergic system in the chicken.

    PubMed

    Ahmed, Abdelkareem A; Ma, Wenqiang; Ni, Yingdong; Zhou, Qin; Zhao, Ruqian

    2014-02-01

    Exposure to excess glucocorticoids (GCs) during embryonic development influences offspring phenotypes and behaviors and induces epigenetic modifications of the genes in the hypothalamic-pituitary-adrenal (HPA) axis and in the serotonergic system in mammals. Whether prenatal corticosterone (CORT) exposure causes similar effects in avian species is less clear. In this study, we injected low (0.2μg) and high (1μg) doses of CORT into developing embryos on day 11 of incubation (E11) and tested the changes in aggressive behavior and hypothalamic gene expression on posthatch chickens of different ages. In ovo administration of high dose CORT significantly suppressed the growth rate from 3weeks of age and increased the frequency of aggressive behaviors, and the dosage was associated with elevated plasma CORT concentrations and significantly downregulated hypothalamic expression of arginine vasotocin (AVT) and corticotropin-releasing hormone (CRH). The hypothalamic content of glucocorticoid receptor (GR) protein was significantly decreased in the high dose group (p<0.05), whereas no changes were observed for GR mRNA. High dose CORT exposure significantly increased platelet serotonin (5-HT) uptake, decreased whole blood 5-HT concentration (p<0.05), downregulated hypothalamic tryptophan hydroxylase 1 (TPH1) mRNA and upregulated 5-HT receptor 1A (5-HTR1A) and monoamine oxidase A (MAO-A) mRNA, but not monoamine oxidase B (MAO-B). High dose CORT also significantly increased DNA methylation of the hypothalamic GR and CRH gene promoters (p<0.05). Our findings suggest that embryonic exposure to CORT programs aggressive behavior in the chicken through alterations of the HPA axis and the serotonergic system, which may involve modifications in DNA methylation.

  2. Long-term effects of early adolescent stress: dysregulation of hypothalamic-pituitary-adrenal axis and central corticotropin releasing factor receptor 1 expression in adult male rats.

    PubMed

    Li, Chuting; Liu, Yuan; Yin, Shiping; Lu, Cuiyan; Liu, Dexiang; Jiang, Hong; Pan, Fang

    2015-07-15

    Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experiences. Studies have found that exposure to early stressful events is a risk factor for developing PTSD. However, a limited number of studies have explored the effects of traumatic stress in early adolescence on behavior, hypothalamic-pituitary-adrenal (HPA) axis function, central corticotropin releasing factor receptor 1 (CRFR1) expression and the relative vulnerability of PTSD in adulthood. The current study aims to explore these issues using inescapable electric foot shock to induce a PTSD model in early adolescent rats. Meanwhile, running on a treadmill for six weeks and administration of the antagonist with 3.2mg/kg/day of CP-154, 526 for 14 consecutive days were used as therapeutic measures. Presently, the stress (S) group showed more anxiety and depression in the open field (OF) test and elevated plus maze (EPM) test, memory damage in the Y maze test, decreased basal CORT level, increased DEX negative feedback inhibition and exacerbated and longer-lasting reaction to CRH challenge in the DEX/CRH test compared with the control group. Central CRFR1 expression was also changed in the S group, as evidenced by the increased CRFR1 expression in the hypothalamus, amygdala and the prefrontal cortex (PFC). However, treadmill exercise alleviated early adolescent stress-induced behavior abnormalities and improved the functional state of the HPA axis, performing a more powerful effect than the CRFR1 antagonist CP-154, 526. Additionally, this study revealed that the alteration of central CRFR1 expression might play an important role in etiology of PTSD in adulthood.

  3. Attenuated hypothalamic-pituitary-adrenal axis functioning predicts accelerated pubertal development in girls 1 year later.

    PubMed

    Saxbe, Darby E; Negriff, Sonya; Susman, Elizabeth J; Trickett, Penelope K

    2015-08-01

    Accelerated pubertal development has been linked to adverse early environments and may heighten subsequent mental and physical health risks. Hypothalamic-pituitary-adrenal axis functioning has been posited as a mechanism whereby stress may affect pubertal development, but the literature lacks prospective tests of this mechanism. The current study assessed 277 youth (M = 10.84 years, SD = 1.14), 138 boys and 139 girls, who reported on their pubertal development and underwent the Trier Social Stress Test for Children at baseline and returned to the laboratory approximately 1 year later (M = 1.12 years, range = 0.59-1.98 years). For girls, lower cortisol area under the curve (with respect to ground) at Time 1 predicted more advanced pubertal development at Time 2, controlling for Time 1 pubertal development. This association persisted after additional covariates including age, body mass index, race, and maltreatment history were introduced, and was driven by adrenal rather than gonadal development. Cortisol was not linked to boys' subsequent pubertal development, and no interaction by gender or by maltreatment appeared. These results suggest that attenuated cortisol, reported in other studies of children exposed to early adversity, may contribute to accelerated pubertal tempo in girls.

  4. Gonadal and Adrenal Abnormalities in Drug Users: Cause or Consequence of Drug Use Behavior and Poor Health Outcomes.

    PubMed

    Brown, Todd T; Wisniewski, Amy B; Dobs, Adrian S

    2006-01-01

    Opiates and cocaine both have effects on adrenal and gonadal function. Opiates suppress the hypothalamic-pituitary adrenal (HPA) axis, whereas cocaine leads to HPA activation. Opiates also cause gonadal dysfunction in both men and women. During withdrawal from opiates and cocaine, the HPA axis is activated which may reinforce relapse behavior. This review describes these hormonal effects and explores the potential consequences, including the effects on mood cognition and cardiovascular risk. Modification of the drug-induced hormonal dysfunction may represent a treatment strategy for drug rehabilitation.

  5. Adrenal androgen excess in the polycystic ovary syndrome: sensitivity and responsivity of the hypothalamic-pituitary-adrenal axis.

    PubMed

    Azziz, R; Black, V; Hines, G A; Fox, L M; Boots, L R

    1998-07-01

    Over 50% of patients with the polycystic ovary syndrome (PCOS) demonstrate excess levels of adrenal androgens (AAs), particularly dehydroepiandrosterone sulfate (DHS). Nonetheless, the mechanism for the AA excess remains unclear. It has been noted that in PCOS the pituitary and ovarian responses to their respective trophic factors (i.e. GnRH and LH, respectively) are exaggerated. Similarly, we have postulated that excess AAs in PCOS arises from dysfunction of the hypothalamic-pituitary-adrenal axis, due to 1) exaggerated pituitary secretion of ACTH in response to hypothalamic CRH, 2) excess sensitivity/responsivity of AAs to ACTH stimulation, or 3) both. To test this hypothesis we studied 12 PCOS patients with AA excess (HI-DHS; DHS, > 8.1 mumol/L or 3000 ng/mL), 12 PCOS patients without AA excess (LO-DHS; DHS, < 7.5 mumol/L or 2750 ng/mL), and 11 controls (normal subjects). Each subject underwent an acute 90-min ovine CRH stimulation test (1 microgram/kg) and an 8-h incremental i.v. stimulation with ACTH-(1-24) at doses ranging from 20-2880 ng/1.5 m2.h) with a final bolus of 0.25 mg. All patient groups had similar mean body mass indexes and ages, and both tests were performed in the morning during the follicular phase (days 3-10) of the same menstrual cycle, separated by 48-96 h. During the acute ovine CRH stimulation test, no significant differences in the net maximal response (i.e. change from baseline to peak level) for ACTH, dehydroepiandrosterone (DHA), androstenedione (A4), or cortisol (F) or for the DHA/ACTH, A4/ACTH, or F/ACTH ratios was observed. Nonetheless, the net response of DHA/F and the areas under the curve (AUCs) for DHA and DHA/F indicated a greater response for HI-DHS vs. LO-DHS or normal subjects. The AUC for A4 and A4/F and the delta A4/delta F ratio (delta = net maximum change) indicated that HI-DHS and LO-DHS had similar responses, which were greater than that of the normal subjects, although the difference between LO-DHS patients and normal

  6. Expression of DAX-1, the gene responsible for X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism, in the hypothalamic-pituitary-adrenal/gonadal axis.

    PubMed

    Guo, W; Burris, T P; McCabe, E R

    1995-10-01

    DAX-1, an orphan member of the nuclear hormone receptor superfamily, is responsible for X-linked adrenal hypoplasia congenita (AHC) and the frequently associated hypogonadotropic hypogonadism (HH). The entire DAX-1 genomic region has been sequenced and a putative steroidogenic factor-1 response element has been identified in the promoter region of the gene. The purpose of these investigations was to determine if DAX-1 was expressed in the central nervous system, particularly the hypothalamus and pituitary, in order to better understand the relationship of mutations in this gene to HH associated with AHC. We used Northern blot analysis and reverse transcription PCR to demonstrate that DAX-1 was expressed in the hypothalamus and the pituitary, and to confirm its expression in adrenal cortex and gonads. The expression of DAX-1 in these tissues indicates the involvement of DAX-1 in the development of the reproductive system at multiple levels within the hypothalamic-pituitary-adrenal/gonadal axis. We also observed the expression of DAX-1 in a human adrenocortical carcinoma cell line, NCI-H295, that has features characteristic of the fetal adrenal cortex. Therefore, NCI-H295 cells will be a useful cellular model for investigating the involvement of DAX-1 in the regulation of steroidogenesis.

  7. Gonadal steroid replacement reverses gonadectomy-induced changes in the corticosterone pulse profile and stress-induced hypothalamic-pituitary-adrenal axis activity of male and female rats.

    PubMed

    Seale, J V; Wood, S A; Atkinson, H C; Harbuz, M S; Lightman, S L

    2004-12-01

    , gonadal steroid replacement reverses stress-induced alterations in hypothalamic-pituitary-adrenal (HPA) activity. These data demonstrate a major contribution of gonadal steroids to the regulation of HPA axis activity and to the pulsatile characteristics of corticosterone release.

  8. Adipose tissue and adrenal glands: novel pathophysiological mechanisms and clinical applications.

    PubMed

    Kargi, Atil Y; Iacobellis, Gianluca

    2014-01-01

    Hormones produced by the adrenal glands and adipose tissues have important roles in normal physiology and are altered in many disease states. Obesity is associated with changes in adrenal function, including increase in adrenal medullary catecholamine output, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, elevations in circulating aldosterone together with changes in adipose tissue glucocorticoid metabolism, and enhanced adipocyte mineralocorticoid receptor activity. It is unknown whether these changes in adrenal endocrine function are in part responsible for the pathogenesis of obesity and related comorbidities or represent an adaptive response. In turn, adipose tissue hormones or "adipokines" have direct effects on the adrenal glands and interact with adrenal hormones at several levels. Here we review the emerging evidence supporting the existence of "cross talk" between the adrenal gland and adipose tissue, focusing on the relevance and roles of their respective hormones in health and disease states including obesity, metabolic syndrome, and primary disorders of the adrenals.

  9. Adipose Tissue and Adrenal Glands: Novel Pathophysiological Mechanisms and Clinical Applications

    PubMed Central

    Kargi, Atil Y.; Iacobellis, Gianluca

    2014-01-01

    Hormones produced by the adrenal glands and adipose tissues have important roles in normal physiology and are altered in many disease states. Obesity is associated with changes in adrenal function, including increase in adrenal medullary catecholamine output, alterations of the hypothalamic-pituitary-adrenal (HPA) axis, elevations in circulating aldosterone together with changes in adipose tissue glucocorticoid metabolism, and enhanced adipocyte mineralocorticoid receptor activity. It is unknown whether these changes in adrenal endocrine function are in part responsible for the pathogenesis of obesity and related comorbidities or represent an adaptive response. In turn, adipose tissue hormones or “adipokines” have direct effects on the adrenal glands and interact with adrenal hormones at several levels. Here we review the emerging evidence supporting the existence of “cross talk” between the adrenal gland and adipose tissue, focusing on the relevance and roles of their respective hormones in health and disease states including obesity, metabolic syndrome, and primary disorders of the adrenals. PMID:25018768

  10. Escitalopram alters gene expression and HPA axis reactivity in rats following chronic overexpression of corticotropin-releasing factor from the central amygdala.

    PubMed

    Flandreau, Elizabeth I; Bourke, Chase H; Ressler, Kerry J; Vale, Wylie W; Nemeroff, Charles B; Owens, Michael J

    2013-08-01

    We have previously demonstrated that viral-mediated overexpression of corticotropin-releasing factor (CRF) within the central nucleus of the amygdala (CeA) reproduces many of the behavioral and endocrine consequences of chronic stress. The present experiment sought to determine whether administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram reverses the adverse effects of CeA CRF overexpression. In a 2×2 design, adult male rats received bilateral infusions of a control lentivirus or a lentivirus in which a portion of the CRF promoter is used to drive increased expression of CRF peptide. Four weeks later, rats were then implanted with an Alzet minipump to deliver vehicle or 10mg/kg/day escitalopram for a 4-week period of time. The defensive withdrawal (DW) test of anxiety and the sucrose-preference test (SPT) of anhedonia were performed both before and after pump implantation. Additional post-implant behavioral tests included the elevated plus maze (EPM) and social interaction (SI) test. Following completion of behavioral testing, the dexamethasone/CRF test was performed to assess HPA axis reactivity. Brains were collected and expression of HPA axis-relevant transcripts were measured using in situ hybridization. Amygdalar CRF overexpression increased anxiety-like behavior in the DW test at week eight, which was only partially prevented by escitalopram. In both CRF-overexpressing and control groups, escitalopram decreased hippocampal CRF expression while increasing hypothalamic and hippocampal expression of the glucocorticoid receptor (GR). These gene expression changes were associated with a significant decrease in HPA axis reactivity in rats treated with escitalopram. Interestingly, escitalopram increased the rate of weight gain only in rats overexpressing CRF. Overall these data support our hypothesis that amygdalar CRF is critical in anxiety-like behavior; because the antidepressant was unable to reverse behavioral manifestations of Ce

  11. The Effects of Smoked Nicotine on Measures of Subjective states and Hypothalamic-Pituitary-Adrenal Axis Hormones in Women during the Follicular and Luteal Phases of the Menstrual Cycle

    PubMed Central

    Goletiani, Nathalie V.; Siegel, Arthur J.; Lukas, Scott E.; Hudson, James I.

    2015-01-01

    Objectives To determine the acute effects of cigarette smoking on hypothalamic-pituitary-adrenal axis (HPA) hormones and subjective states as a function of the menstrual cycle in nicotine-dependent women. Methods Seventeen healthy nicotine-dependent women were studied during the follicular and/or luteal phase of the menstrual cycle. Due to observation of a possible bimodal distribution of progesterone levels within the luteal phase group, we performed a set of a posteriori analyses. Therefore, we divided the luteal group into a low progesterone and a high progesterone groups. Results Smoked nicotine activated HPA, measured by ACTH, cortisol, and DHEA response and affected subjective states in both follicular and luteal phases, with increased “High”, “Rush”, and decreased “Craving”. The HPA stimulation revealed a blunting of ACTH response. There was only modest evidence for a blunting of subjective state responses in the luteal phase. However upon post hoc analyses, the high progesterone luteal group showed a marked blunting of measures of subjective states and a blunted ACTH response. Examining the association between hormone and measures of subjective states revealed tentative associations of ACTH stimulation with increased “Rush” and “Craving”, and DHEA stimulation with increased “Craving”. Conclusions This pilot study suggests that menstrual cycle phase differences in progesterone levels may attenuate nicotine’s addictive effects via diminution of its reinforcing properties, and augmentation of its aversive effects interfering with the pleasure associated with cigarette smoking. PMID:25783522

  12. Paternal preconception ethanol exposure blunts hypothalamic-pituitary-adrenal axis responsivity and stress-induced excessive fluid intake in male mice.

    PubMed

    Rompala, Gregory R; Finegersh, Andrey; Homanics, Gregg E

    2016-06-01

    A growing number of environmental insults have been shown to induce epigenetic effects that persist across generations. For instance, paternal preconception exposures to ethanol or stress have independently been shown to exert such intergenerational effects. Since ethanol exposure is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that paternal ethanol exposure would impact stress responsivity of offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. Adult male and female offspring were tested for plasma corticosterone (CORT) levels following acute restraint stress and the male offspring were further examined for stress-evoked 2-bottle choice ethanol-drinking. Paternal ethanol exposure blunted plasma CORT levels following acute restraint stress selectively in male offspring; females were unaffected. In a stress-evoked ethanol-drinking assay, there was no effect of stress on ethanol consumption. However, C-sired males exhibited increased total fluid intake (polydipsia) in response to stress while E-sired males were resistant to this stress-induced phenotype. Taken together, these data suggest that paternal ethanol exposure imparts stress hyporesponsivity to male offspring.

  13. The Moderating Role of Sensory Overresponsivity in HPA Activity: A Pilot Study with Children Diagnosed with ADHD

    ERIC Educational Resources Information Center

    Reynolds, Stacey; Lane, Shelly J.; Gennings, Chris

    2010-01-01

    Objective: To determine if sensory overresponsivity (SOR) is a moderating condition impacting the activity of the Hypothalamic Pituitary Adrenal (HPA) Axis in children with ADHD. Method: Participants were children with (n = 24) and without ADHD (n = 24). Children in the ADHD group were divided into SOR (ADHDs) and non-SOR (ADHDt) groups using the…

  14. HPA axis response to social stress is attenuated in schizophrenia but normal in depression: evidence from a meta-analysis of existing studies.

    PubMed

    Ciufolini, Simone; Dazzan, Paola; Kempton, Matthew J; Pariante, Carmine; Mondelli, Valeria

    2014-11-01

    We conducted a meta-analysis to investigate the HPA axis response to social stress in studies that used the Trier Social Stress Test (TSST), or comparable distressing paradigms, in individuals with either depression or schizophrenia. Sample size-adjusted effect sizes (Hedge's g statistic) were calculated to estimate the HPA axis stress response to social stress. We used a meta-regression model to take into account the moderating effect of the baseline cortisol level. Participants with depression show an activation pattern to social stress similar to that of healthy controls. Despite a normal cortisol production rate, individuals with schizophrenia have lower cortisol levels than controls both in anticipation and after exposure to social stress. Participants with depression and higher cortisol levels before the task have an increased cortisol production and reached higher cortisol levels during the task. This may be explained by the presence of an impaired negative feedback. The activation pattern present in schizophrenia may explain the reduced ability to appropriately contextualize past experiences shown by individuals with psychosis in social stressful situation.

  15. Suckling and salsolinol attenuate responsiveness of the hypothalamic-pituitary-adrenal axis to stress: focus on catecholamines, corticotrophin-releasing hormone, adrenocorticotrophic hormone, cortisol and prolactin secretion in lactating sheep.

    PubMed

    Hasiec, M; Tomaszewska-Zaremba, D; Misztal, T

    2014-12-01

    In mammals, the responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis to stress is reduced during lactation and this mainly results from suckling by the offspring. The suckling stimulus causes a release of the hypothalamic 1-metyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol) (a derivative of dopamine), one of the prolactin-releasing factors. To investigate the involvement of salsolinol in the mechanism suppressing stress-induced HPA axis activity, we conducted a series of experiments on lactating sheep, in which they were treated with two kinds of isolation stress (isolation from the flock with lamb present or absent), combined with suckling and/or i.c.v infusion of salsolinol and 1-methyl-3,4-dihydro-isoqinoline (1-MeDIQ; an antagonistic analogue of salsolinol). Additionally, a push-pull perfusion of the infundibular nucleus/median eminence (IN/ME) and blood sample collection with 10-min intervals were performed during the experiments. Concentrations of perfusate corticotrophin-releasing hormone (CRH) and catecholamines (noradrenaline, dopamine and salsolinol), as well as concentrations of plasma adenocorticotrophic hormone (ACTH), cortisol and prolactin, were assayed. A significant increase in perfusate noradrenaline, plasma ACTH and cortisol occurred in response to both kinds of isolation stress. Suckling and salsolinol reduced the stress-induced increase in plasma ACTH and cortisol concentrations. Salsolinol also significantly reduced the stress-induced noradrenaline and dopamine release within the IN/ME. Treatment with 1-MeDIQ under the stress conditions significantly diminished the salsolinol concentration and increased CRH and cortisol concentrations. Stress and salsolinol did not increase the plasma prolactin concentration, in contrast to the suckling stimulus. In conclusion, salsolinol released in nursing sheep may have a suppressing effect on stress-induced HPA axis activity and peripheral prolactin does not appear to participate in

  16. Differentiation of Keratinocytes Modulates Skin HPA Analog.

    PubMed

    Wierzbicka, Justyna M; Żmijewski, Michał A; Antoniewicz, Jakub; Sobjanek, Michal; Slominski, Andrzej T

    2017-01-01

    It is well established, that epidermal keratinocytes express functional equivalent of hypothalamus-pituitary-adrenal axis (HPA) in order to respond to changing environment and maintain internal homeostasis. We are presenting data indicating that differentiation of primary neonatal human keratinocytes (HPEKp), induced by prolonged incubation or calcium is accompanied by significant changes in the expression of the elements of skin analog of HPA (sHPA). Expression of CRF, UCN1-3, POMC, ACTH, CRFR1, CRFR2, MC1R, MC2R, and GR (coded by NR3C1 gene) were observed on gene/protein levels along differentiation of keratinocytes in culture with similar pattern seen by immunohistochemistry on full thickness skin biopsies. Expression of CRF was more pronounced in less differentiated keratinocytes, which corresponded to the detection of CRF immunoreactivity preferentially in the stratum basale. POMC expression was enhanced in more differentiated keratinocytes, which corresponded to detection of ACTH immunoreactivity, predominantly in the stratum spinosum and stratum granulosum. Expression of urocortins was also affected by induction of HPEKp differentiation. Immunohistochemical studies showed high prevalence of CRFR1 in well differentiated keratinocytes, while smaller keratinocytes showed predominantly CRFR2 immunoreactivity. MC2R mRNA levels were elevated from days 4 to 8 of in vitro incubation, while MC2R immunoreactivity was the highest in the upper layers of epidermis. Similar changes in mRNA/protein levels of sHPA elements were observed in HPEKp keratinocytes treated with calcium. Summarizing, preferential expression of CRF and POMC (ACTH) by populations of keratinocytes on different stage of differentiation resembles organization of central HPA axis suggesting their distinct role in physiology and pathology of the epidermis. J. Cell. Physiol. 232: 154-166, 2017. © 2016 Wiley Periodicals, Inc.

  17. Adrenal insufficiency.

    PubMed

    Li-Ng, Melissa; Kennedy, Laurence

    2012-10-01

    Adrenocortical insufficiency may arise through primary failure of the adrenal glands or due to lack of ACTH stimulation as a result of pituitary or hypothalamic dysfunction. Prolonged administration of exogenous steroids will suppress the hypothalamic-pituitary-adrenal axis, and hence cortisol secretion. We review briefly the causes, investigation, and treatment of adrenal insufficiency, and highlight aspects of particular relevance to patients with adrenal tumors.

  18. Prolonged activation of the hypothalamus-pituitary-gonadal axis in a child with X-linked adrenal hypoplasia congenita.

    PubMed

    Takahashi, I; Takahashi, T; Shoji, Y; Takada, G

    2000-07-01

    X-linked adrenal hypoplasia congenita (AHC) is a rare developmental disorder of the human adrenal cortex that is caused by a mutation of the DAX-1 gene, a member of the nuclear hormone receptor superfamily. Hypogonadotrophic hypogonadism is frequently associated with this disease and the DAX-1 mutation is known to impair gonadotrophin production by acting at both the hypothalamic and pituitary levels. However, three recent studies reported that the hypothalamic-pituitary-gonadal axis was active in six infants with AHC, suggesting that a difference exists in the central regulation of hypothalamic-pituitary-gonadal activity between infant boys and pubertal boys. To determine the effect of the DAX-1 gene mutation on the axis in early childhood, we measured testosterone, LH, and FSH and performed LH-releasing hormone tests on a boy with AHC from birth to 3 years of age. Surprisingly, our findings showed that the axis was active from the infantile period to 3 years of age. This delayed initiation of the prepubertal pause, or prolonged activation of the axis, indicates that the DAX-1 gene is related to the control mechanism of the prepubertal restraint of gonadotrophin secretion.

  19. Effects of an exercise and hypocaloric healthy eating intervention on indices of psychological health status, hypothalamic-pituitary-adrenal axis regulation and immune function after early-stage breast cancer: a randomised controlled trial

    PubMed Central

    2014-01-01

    Introduction Many women experience emotional distress, depression and anxiety after a diagnosis of breast cancer. Psychological stress and depression have been associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation that may adversely affect immune system functioning and impact upon survival. This study investigated the effects of a lifestyle intervention on indices of psychological health status, HPA axis regulation and immune function in overweight women recovering from early-stage breast cancer treatment. Methods A total of 85 women treated for breast cancer 3 to 18 months previously were randomly allocated to a 6-month exercise and hypocaloric healthy eating program plus usual care or usual care alone (control group). Women in the intervention group received three supervised exercise sessions per week and individualized dietary advice, supplemented by weekly nutrition seminars. Depressive symptoms (Beck Depression Inventory version II: BDI-II), perceived stress (Perceived Stress Scale: PSS), salivary diurnal cortisol rhythms; inflammatory cytokines (IL-6 and Tumor necrosis factor-α), leukocyte phenotype counts, natural killer (NK) cell cytotoxicity and lymphocyte proliferation following mitogenic stimulation were assessed at baseline and 6-month follow up. Results Compared with the control group, the intervention group exhibited a reduction in depressive symptoms (adjusted mean difference, 95% confidence intervals (95% CI): −3.12, −1.03 to −5.26; P = 0.004) at the 6-month follow-up but no significant decrease in PSS scores (−2.07, −4.96 to 0.82; P = 0.16). The lifestyle intervention also had a significant impact on diurnal salivary cortisol rhythm compared with usual care alone, as evidenced by an increase in morning salivary cortisol at the 6-month follow-up (P <0.04), indicating a change in HPA axis regulation. Women in the control group had higher total leukocyte, neutrophil and lymphocyte counts in comparison to the

  20. PCOS: an ovarian disorder that leads to dysregulation in the hypothalamic-pituitary-adrenal axis?

    PubMed

    Doi, Suhail A R; Towers, Philip A; Scott, Christopher J; Al-Shoumer, Kamal A S

    2005-01-10

    This review focuses on the role of the ovaries in the pathogenesis of the polycystic ovarian syndrome. In particular, the failure of follicular development, hypothalamo-pituitary dysregulation, alterations in adrenal steroid output and derangement of intermediary metabolism are discussed in the context of the ovaries. It is concluded that the central and adrenal alterations associated with PCOS are unlikely to be primary but rather are secondary to the events within the ovary.

  1. Primary symptomatic adrenal insufficiency induced by megestrol acetate.

    PubMed

    Delitala, A P; Fanciulli, G; Maioli, M; Piga, G; Delitala, G

    2013-01-01

    Megestrol acetate (MA) is a progestational agent for the treatment of metastatic breast cancer and endometrial cancer. MA has also been used to promote weight gain in malnourished elderly patients, in patients with immunodeficiency virus and in cancer-induced cachexia. In addition to thromboembolic disease, MA may induce hyperglycaemia, osteoporosis, suppression of the gonadal axis, and Cushing's syndrome. MA has also been shown to cause symptomatic suppression of the hypothalamic-pituitary-adrenal (HPA) axis owing to its intrinsic glucocorticoid-like effect. Three additional patients are presented who developed symptomatic adrenal insufficiency while they were receiving 160-320 mg MA daily. The patients were treated with cortisone acetate supplements, had clear evidence of HPA-axis suppression but recovered fully after MA was discontinued. Patients receiving MA might have an inadequate adrenal response during stressful conditions, possibly because 160-320 mg MA daily may not provide adequate protection to prevent the symptoms of adrenal insufficiency. The adverse MA effect on the HPA axis is probably not well recognised in clinical practice, and clinicians need an increased awareness of the endocrine complications secondary to MA treatment.

  2. Adrenal insufficiency in patients with decompensated cirrhosis

    PubMed Central

    Karagiannis, Apostolos KA; Nakouti, Theodora; Pipili, Chrysoula; Cholongitas, Evangelos

    2015-01-01

    Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary-adrenal (HPA) axis are causes for adrenal insufficiency (AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI in cirrhotics as well. Both stable cirrhotics and liver transplant patients (early and later after transplantation) have been reported to present AI. The mechanisms leading to reduced cortisol production in cirrhotics are the combination of low cholesterol levels (the primary source of cortisol), the increased cytokines production that overstimulate and exhaust HPA axis and the destruction of adrenal glands due to coagulopathy. AI has been recorded in 10%-82% cirrhotics depending on the test used to evaluate adrenal function and in 9%-83% stable cirrhotics. The similarity of those proportions support the assumption that AI is an endogenous characteristic of liver disease. However, the lack of a gold standard method for AI assessment and the limitation of precise thresholds in cirrhotics make difficult the recording of the real prevalence of AI. This review aims to summarize the present data over AI in stable, critically ill cirrhotics and liver transplant recipients. Moreover, it provides information about the current knowledge in the used diagnostic tools and the possible effectiveness of corticosteroids administration in critically ill cirrhotics with AI. PMID:26052400

  3. Hypothalamus-Pituitary-Adrenal Axis, Hair Cortisol and the Metabolic Syndrome.

    PubMed

    Gaete, Helen Patricia

    2015-09-01

    In this paper we discuss the possibility of using Hair Cortisol in Clinical Practice to monitor HPA status in patents at risk of developing the Metabolic Syndrome, and also its possible use to assess effectiveness of the effectiveness of treatment in patients with the Metabolic Syndrome. PMID:26417828

  4. Highly Palatable Food during Adolescence Improves Anxiety-Like Behaviors and Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Rats that Experienced Neonatal Maternal Separation

    PubMed Central

    Lee, Jong-Ho; Kim, Jin Young

    2014-01-01

    Background This study was conducted to examine the effects of ad libitum consumption of highly palatable food (HPF) during adolescence on the adverse behavioral outcome of neonatal maternal separation. Methods Male Sprague-Dawley pups were separated from dam for 3 hours daily during the first 2 weeks of birth (maternal separation, MS) or left undisturbed (nonhandled, NH). Half of MS pups received free access to chocolate cookies in addition to ad libitum chow from postnatal day 28 (MS+HPF). Pups were subjected to behavioral tests during young adulthood. The plasma corticosterone response to stress challenge was analyzed by radioimmunoassay. Results Daily caloric intake and body weight gain did not differ among the experimental groups. Ambulatory activities were decreased defecation activity and rostral grooming were increased in MS controls (fed with chow only) compared with NH rats. MS controls spent less time in open arms, and more time in closed arms during the elevated plus maze test, than NH rats. Immobility duration during the forced swim test was increased in MS controls compared with NH rats. Cookie access normalized the behavioral scores of ambulatory and defecation activities and grooming, but not the scores during the elevated plus maze and swim tests in MS rats. Stress-induced corticosterone increase was blunted in MS rats fed with chow only, and cookie access normalized it. Conclusion Prolonged access to HPF during adolescence and youth partly improves anxiety-related, but not depressive, symptoms in rats that experienced neonatal maternal separation, possibly in relation with improved function of the hypothalamic-pituitary-adrenal (HPA) axis. PMID:25031890

  5. Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats.

    PubMed

    Vargas, Javier; Junco, Mariana; Gomez, Carlos; Lajud, Naima

    2016-01-01

    Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that

  6. Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats.

    PubMed

    Vargas, Javier; Junco, Mariana; Gomez, Carlos; Lajud, Naima

    2016-01-01

    Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that

  7. Early Life Stress Increases Metabolic Risk, HPA Axis Reactivity, and Depressive-Like Behavior When Combined with Postweaning Social Isolation in Rats

    PubMed Central

    Vargas, Javier; Junco, Mariana; Gomez, Carlos; Lajud, Naima

    2016-01-01

    Early-life stress is associated with depression and metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. Such associations could be due to increased glucocorticoid levels. Periodic maternal separation in the neonate and rearing in social isolation are potent stressors that increase hypothalamus-pituitary-adrenal axis activity. Moreover, social isolation promotes feed intake and body weight gain in rats subjected to periodic maternal separation; however, its effects on metabolic risks have not been described. In the present study, we evaluated whether periodic maternal separation, social isolation rearing, and a combination of these two stressors (periodic maternal separation + social isolation rearing) impair glucose homeostasis and its relation to the hypothalamus-pituitary-adrenal axis and depressive-like behavior. Periodic maternal separation increased basal corticosterone levels, induced a passive coping strategy in the forced swimming test, and was associated with a mild (24%) increase in fasting glucose, insulin resistance, and dyslipidemia. Rearing in social isolation increased stress reactivity in comparison to both controls and in combination with periodic maternal separation, without affecting the coping strategy associated with the forced swimming test. However, social isolation also increased body weight gain, fasting glucose (120%), and insulin levels in rats subjected to periodic maternal separation. Correlation analyses showed that stress-induced effects on coping strategy on the forced swimming test (but not on metabolic risk markers) are associated with basal corticosterone levels. These findings suggest that maternal separation and postweaning social isolation affect stress and metabolic vulnerability differentially and that early-life stress-related effects on metabolism are not directly dependent on glucocorticoid levels. In conclusion, our study supports the cumulative stress hypothesis, which suggests that

  8. Menstrual bleeding in a female infant with congenital adrenal hyperplasia: altered maturation of the hypothalamic-pituitary-ovarian axis.

    PubMed

    Uli, N; Chin, D; David, R; Geneiser, N; Roche, K; Marino, F; Shapiro, E; Prasad, K; Oberfield, S

    1997-10-01

    Vaginal bleeding during the neonatal period is commonly related to the withdrawal of maternal estrogens. Vaginal bleeding has also been reported in female infants with congenital adrenal hyperplasia and has been proposed to be due to a treatment-induced activation of the hypothalamic-pituitary-ovarian axis. We report a female infant with the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, who had the onset of vaginal bleeding at 3 months of life. Adrenal steroid suppression had been achieved by 2.5 weeks of age. At the time of bleeding, imaging studies revealed an enlarged right ovary with a dominant 3-cm cyst and additional small cysts that had not been seen on the newborn sonogram. The uterus was enlarged and stimulated. Three weeks later (1 week after the cessation of bleeding), repeat ultrasound demonstrated a marked decrease in the size of the right ovary, and the dominant cyst was no longer seen. The patient had a heightened FSH response to GnRH and elevated levels of estradiol for age. At 5 months of age, no further episodes of sustained vaginal bleeding were observed. Repeat hormonal levels were prepubertal, and pelvic sonogram demonstrated no evidence of stimulation. The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels, which then triggered a transient and augmented end-organ response (menses). Further, we suggest that our infant's hormonal findings may reflect a delay in the timely development of the negative restraint by sex steroids on gonadotropins that is normally observed in infancy.

  9. Effects of escitalopram/quetiapine combination therapy versus escitalopram monotherapy on hypothalamic-pituitary-adrenal-axis activity in relation to antidepressant effectiveness.

    PubMed

    Nothdurfter, Caroline; Schmotz, Christian; Sarubin, Nina; Baghai, Thomas C; Laenger, Anna; Lieb, Martin; Bondy, Brigitta; Rupprecht, Rainer; Schüle, Cornelius

    2014-05-01

    The hypothalamic-pituitary-adrenocortical (HPA) system is believed to play an important role in the pathophysiology of major depressive disorder. In this context, the atypical antipsychotic quetiapine (QUE) has been shown to inhibit HPA system activity in healthy subjects. In this study we investigated whether the putative inhibitory effects of QUE on HPA system activity may contribute to its antidepressant efficacy. We analyzed the effects of QUE as an augmentation to the selective serotonin reuptake inhibitor (SSRI) escitalopram (ESC) on HPA system activity in comparison to a monotherapy with ESC in relation to the antidepressant effectiveness. HPA axis activity (cortisol and ACTH) was measured by means of the dexamethasone/corticotropin-releasing hormone (DEX/CRH) test which was performed before (week 0) and during (week 1, week 5) antidepressant psychopharmacotherapy. The combination therapy, but not the ESC monotherapy showed significantly inhibiting effects on HPA system activity leading to stepwise down-regulation. ACTH concentrations were reduced in the ESC/QUE group during five weeks of treatment. The inhibitory effect of QUE maybe involved in its antidepressant effects as an augmentation strategy.

  10. Association of BDNF Val66Met polymorphism with HPA and SAM axis reactivity to psychological and physical stress

    PubMed Central

    Tsuru, Jusen; Tanaka, Yoshihiro; Ishitobi, Yoshinobu; Maruyama, Yoshihiro; Inoue, Ayako; Kawano, Aimi; Ikeda, Rie; Ando, Tomoko; Oshita, Harumi; Aizawa, Saeko; Masuda, Koji; Higuma, Haruka; Kanehisa, Masayuki; Ninomiya, Taiga; Akiyoshi, Jotaro

    2014-01-01

    Background Decreased expression of brain-derived neurotrophic factor (BDNF) is implicated in enhanced stress responses. The BDNF Val66Met polymorphism is associated with psychological changes; for example, carriers of the Met allele exhibit increased harm avoidance as well as a higher prevalence of depression and anxiety disorder. Methods To analyze the effects of BDNF Val66Met on stress responses, we tested 226 university students (88 women and 138 men) using a social stress procedure (Trier Social Stress Test [TSST]) and an electrical stimulation stress test. Stress indices were derived from repeated measurements of salivary α-amylase, salivary cortisol, heart rate, and psychological testing during the stress tests. All subjects were genotyped for the Val66Met polymorphism (G196A). Results A significant three-way interaction (time [3 levels] × BDNF [Val/Val, Val/Met, Met/Met]; P<0.05) was demonstrated that revealed different salivary cortisol responses in the TSST but not in electrical stimulation. Met/Met women had stronger cortisol responses than Val/Met and Val/Val individuals in the TSST. Met/Met men exhibited stronger salivary cortisol responses than Val/Met and Val/Val individuals in the TSST. Conclusion These results indicate that a common, functionally significant polymorphism in BDNF had different effects on hypothalamic–pituitary–adrenocortical axis reactivity but not on sympathetic adrenomedullary reactivity in TSST and electrical stimulation tests. PMID:25419135

  11. A short-term extremely low frequency electromagnetic field exposure increases circulating leukocyte numbers and affects HPA-axis signaling in mice.

    PubMed

    de Kleijn, Stan; Ferwerda, Gerben; Wiese, Michelle; Trentelman, Jos; Cuppen, Jan; Kozicz, Tamas; de Jager, Linda; Hermans, Peter W M; Verburg-van Kemenade, B M Lidy

    2016-10-01

    There is still uncertainty whether extremely low frequency electromagnetic fields (ELF-EMF) can induce health effects like immunomodulation. Despite evidence obtained in vitro, an unambiguous association has not yet been established in vivo. Here, mice were exposed to ELF-EMF for 1, 4, and 24 h/day in a short-term (1 week) and long-term (15 weeks) set-up to investigate whole body effects on the level of stress regulation and immune response. ELF-EMF signal contained multiple frequencies (20-5000 Hz) and a magnetic flux density of 10 μT. After exposure, blood was analyzed for leukocyte numbers (short-term and long-term) and adrenocorticotropic hormone concentration (short-term only). Furthermore, in the short-term experiment, stress-related parameters, corticotropin-releasing hormone, proopiomelanocortin (POMC) and CYP11A1 gene-expression, respectively, were determined in the hypothalamic paraventricular nucleus, pituitary, and adrenal glands. In the short-term but not long-term experiment, leukocyte counts were significantly higher in the 24 h-exposed group compared with controls, mainly represented by increased neutrophils and CD4 ± lymphocytes. POMC expression and plasma adrenocorticotropic hormone were significantly lower compared with unexposed control mice. In conclusion, short-term ELF-EMF exposure may affect hypothalamic-pituitary-adrenal axis activation in mice. Changes in stress hormone release may explain changes in circulating leukocyte numbers and composition. Bioelectromagnetics. 37:433-443, 2016. © 2016 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc. PMID:27553635

  12. Antidepressant-like effects of salidroside on olfactory bulbectomy-induced pro-inflammatory cytokine production and hyperactivity of HPA axis in rats.

    PubMed

    Yang, Shui-Jin; Yu, Hai-Yang; Kang, Dan-Yu; Ma, Zhan-Qiang; Qu, Rong; Fu, Qiang; Ma, Shi-Ping

    2014-09-01

    Salidroside (SA) is the primary bioactive marker compound in the standardized extracts from Rhodiola rosea. Although it has potential antidepressant activity in a rat behavioral despair model, the mechanisms of antidepressant effect for SA remain unclear. The objective of this study was to evaluate the antidepressant effects of SA and to discuss the potential mechanisms in olfactory bulbectomized (OBX) rats. SA of 20, 40 mg/kg (p.o.) for 2 weeks notably alleviated OBX-induced hyperactivity in open field test, decreased immobility time in TST and FST. Chronic treatment with SA could remarkably reduce TNF-α and IL-1β levels in hippocampus. Western blot showed that SA could markedly increase glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Besides, SA could also attenuate corticotropin-releasing hormone (CRH) expression in hypothalamus, as well as reducing significantly the levels of serum corticosterone. In conclusion, this study demonstrated that OBX rats treated with SA could significantly improve the depressive-like behaviors. The antidepressant mechanisms of SA might be associated with its anti-inflammatory effects and the regulation of HPA axis activity. Reversal of abnormalities of GR may be partly responsible for those effects. These findings suggested that SA might become a beneficial agent to prevent and treat the depression. PMID:25101546

  13. The effect of trans-resveratrol on post-stroke depression via regulation of hypothalamus-pituitary-adrenal axis.

    PubMed

    Pang, Cong; Cao, Liang; Wu, Fan; Wang, Li; Wang, Gang; Yu, Yingcong; Zhang, Meixi; Chen, Lichao; Wang, Weijie; Lv, Weihong; Chen, Ling; Zhu, Jiejin; Pan, Jianchun; Zhang, Hanting; Xu, Ying; Ding, Lianshu

    2015-10-01

    Post-stroke depression (PSD) occurs about 40% among all stroke survivors, but the effective pharmacotherapy is inadequately understood. The present study investigated the effects of a natural polyphenol trans-resveratrol (RES) on behavioral changes after middle cerebral artery occlusion (MCAO) and examined what its molecular targets may be. RES was shown to decrease the infarct size and neurological scores after MCAO, suggesting the amelioration of brain damage and motor activity. RES also reversed the depressive-like behaviors 13 days after MCAO, both in the forced swimming and sucrose consumption tests. Moreover, MCAO-induced series abnormalities related to depressive-like behaviors, such as an abnormal adrenal gland weight to body weight ratio, an increased expression of the corticotropin-releasing factor (CRF) in the frontal cortex, hippocampus and hypothalamus, the differential expression of glucocorticoid receptor (GR) in these three brain regions, and a decreased brain-derived neurotrophic factor (BDNF) level, were ameliorated after treatment with increasing doses of RES at 10, 20 and 40 mg/kg via gavage. These findings provide compelling evidence that RES protects the brain against focal cerebral ischemia-induced injury, but most of all is its antidepressant-like effect on PSD, which might at least in part be mediated by regulation of hypothalamus-pituitary-adrenal axis function. PMID:25937213

  14. Hypothalamic-pituitary-adrenal and -gonadal axis function after exercise in sedentary and endurance trained elderly males.

    PubMed

    Strüder, H K; Hollmann, W; Platen, P; Rost, R; Weicker, H; Weber, K

    1998-02-01

    The aim of this study was to investigate hypothalamic-pituitary-adrenal (HPAA) and -gonadal (HPGA) axis responses to post-exercise (30 min at 65% VO2max) combined corticotrophin, luteinizing hormone and thyrotrophin releasing hormone challenge (0.7 microg/ kg body mass) in elderly distance runners (DR; age: 68.9+/-4.2 year) and sedentary individuals (SI; age: 69.1+/-2.6 year). Plasma cortisol, growth hormone, prolactin, luteinizing hormone, follicle stimulating hormone and total testosterone (T) concentrations pre- and post-exercise as well as in response to stimulation did not differ between DR and SI. Plasma adrenocorticotropic hormone returned to pre-exercise level in DR 60 min and in SI 90 min post-stimulation. Free T was lower in DR at all time points. Our results do not support the notion of altered releasing hormone-stimulable HPAA and HPGA synthesis-secretion capacity in elderly males after endurance training.

  15. The hypothalamic-pituitary-adrenal axis and sex hormones in chronic stress and obesity: pathophysiological and clinical aspects.

    PubMed

    Pasquali, Renato

    2012-08-01

    Obesity, particularly the abdominal phenotype, has been ascribed to an individual maladaptation to chronic environmental stress exposure mediated by a dysregulation of related neuroendocrine axes. Alterations in the control and action of the hypothalamic-pituitary-adrenal axis play a major role in this context, with the participation of the sympathetic nervous system. The ability to adapt to chronic stress may differ according to sex, with specific pathophysiological events leading to the development of stress-related chronic diseases. This seems to be influenced by the regulatory effects of sex hormones, particularly androgens. Stress may also disrupt the control of feeding, with some differences according to sex. Finally, the amount of experimental data in both animals and humans may help to shed more light on specific phenotypes of obesity, strictly related to the chronic exposure to stress. This challenge may potentially imply a different pathophysiological perspective and, possibly, a specific treatment.

  16. Antidepressant-like activity of resveratrol treatment in the forced swim test and tail suspension test in mice: the HPA axis, BDNF expression and phosphorylation of ERK.

    PubMed

    Wang, Zhen; Gu, Jianhua; Wang, Xueer; Xie, Kai; Luan, Qinsong; Wan, Nianqing; Zhang, Qun; Jiang, Hong; Liu, Dexiang

    2013-11-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has diverse biological activities. There is only limited information about the antidepressant-like effect of resveratrol. The present study assessed whether resveratrol treatment (20, 40 and 80mg/kg, i.p., 21days) has an antidepressant-like effect on the forced swim test (FST) and tail suspension test (TST) in mice and examined what its molecular targets might be. The results showed that resveratrol administration produced antidepressant-like effects in mice, evidenced by the reduced immobility time in the FST and TST, while it had no effect on the locomotor activity in the open field test. Resveratrol treatment significantly reduced serum corticosterone levels, which had been elevated by the FST and TST. Moreover, resveratrol increased brain-derived neurotrophic factor (BDNF) protein and extracellular signal-regulated kinase (ERK) phosphorylation levels in the prefrontal cortex and hippocampus. All of these antidepressant-like effects of resveratrol were essentially similar to those observed with the clinical antidepressant, fluoxetine. These results suggest that the antidepressant-like effects of resveratrol in the FST and TST are mediated, at least in part, by modulating hypothalamic-pituitary-adrenal axis, BDNF and ERK phosphorylation expression in the brain region of mice. PMID:24125781

  17. Antidepressant-like activity of resveratrol treatment in the forced swim test and tail suspension test in mice: the HPA axis, BDNF expression and phosphorylation of ERK.

    PubMed

    Wang, Zhen; Gu, Jianhua; Wang, Xueer; Xie, Kai; Luan, Qinsong; Wan, Nianqing; Zhang, Qun; Jiang, Hong; Liu, Dexiang

    2013-11-01

    Resveratrol is a natural polyphenol enriched in Polygonum cuspidatum and has diverse biological activities. There is only limited information about the antidepressant-like effect of resveratrol. The present study assessed whether resveratrol treatment (20, 40 and 80mg/kg, i.p., 21days) has an antidepressant-like effect on the forced swim test (FST) and tail suspension test (TST) in mice and examined what its molecular targets might be. The results showed that resveratrol administration produced antidepressant-like effects in mice, evidenced by the reduced immobility time in the FST and TST, while it had no effect on the locomotor activity in the open field test. Resveratrol treatment significantly reduced serum corticosterone levels, which had been elevated by the FST and TST. Moreover, resveratrol increased brain-derived neurotrophic factor (BDNF) protein and extracellular signal-regulated kinase (ERK) phosphorylation levels in the prefrontal cortex and hippocampus. All of these antidepressant-like effects of resveratrol were essentially similar to those observed with the clinical antidepressant, fluoxetine. These results suggest that the antidepressant-like effects of resveratrol in the FST and TST are mediated, at least in part, by modulating hypothalamic-pituitary-adrenal axis, BDNF and ERK phosphorylation expression in the brain region of mice.

  18. Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes.

    PubMed

    Viau, V

    2002-06-01

    Under normal conditions, the adrenal glucocorticoids, the endproduct of the hypothalamic-pituitary-adrenal (HPA) axis, provide a frontline of defence against threats to homeostasis (i.e. stress). On the other hand, chronic HPA drive and glucocorticoid hypersecretion have been implicated in the pathogenesis of several forms of systemic, neurodegenerative and affective disorders. The HPA axis is subject to gonadal influence, indicated by sex differences in basal and stress HPA function and neuropathologies associated with HPA dysfunction. Functional cross-talk between the gonadal and adrenal axes is due in large part to the interactive effects of sex steroids and glucocorticoids, explaining perhaps why several disease states linked to stress are sex-dependent. Realizing the interactive nature by which the hypothalamic-pituitary-gonadal and HPA systems operate, however, has made it difficult to model how these hormones act in the brain. Manipulation of one endocrine system is not without effects on the other. Simultaneous manipulation and assessment of both endocrine systems can overcome this problem. This dual approach in the male rat reveals that testosterone can act and interact on different aspects of basal and stress HPA function. Basal adrenocorticotropic hormone (ACTH) release is regulated by testosterone-dependent effects on arginine vasopressin synthesis, and corticosterone-dependent effects on corticotropin-releasing hormone (CRH) synthesis in the paraventricular nucleus (PVN) of the hypothalamus. In contrast, testosterone and corticosterone interact on stress-induced ACTH release and drive to the PVN motor neurones. Candidate structures mediating this interaction include several testosterone-sensitive afferents to the HPA axis, including the medial preoptic area, central and medial amygdala and bed nuclei of the stria terminalis. All of these relay homeostatic information and integrate reproductive and social behaviour. Because these modalities are affected

  19. Pubertal maturation and programming of hypothalamic-pituitary-adrenal reactivity.

    PubMed

    Romeo, Russell D

    2010-04-01

    Modifications in neuroendocrine function are a hallmark of pubertal development. These changes have many short- and long-term implications for the physiological and neurobehavioral function of an individual. The purpose of the present review is to discuss our current understanding of how pubertal development and stress interact to affect the hypothalamic-pituitary-adrenal (HPA) axis, the major neuroendocrine axis that controls the hormonal stress response. A growing body of literature indicates that puberty is marked by dramatic transitions in stress reactivity. Moreover, recent studies indicate that exposure to stressors during pubertal maturation may result in enduring changes in HPA responsiveness in adulthood. As puberty is marked by a substantial increase in many stress-related psychological and physiological disorders (e.g., depression, anxiety, drug abuse), it is essential to understand the factors that regulate and modulate HPA function during this crucial period of development.

  20. Repeated administrations of adrenocorticotropic hormone during late gestation in pigs: maternal cortisol response and effects on fetal HPA axis and brain neurotransmitter systems.

    PubMed

    Otten, W; Kanitz, E; Tuchscherer, M; Brüssow, K-P; Nürnberg, G

    2008-02-01

    The present study examined the effects of repeated adrenocorticotropic hormone (ACTH) administrations to sows during late gestation on hypothalamic-pituitary-adrenocortical (HPA) axis and brain neurotransmitter systems in their fetuses. ACTH (100 IU per animal, Synacthen Depot, n=6) or saline (n=5) was administered intramuscularly to sows every 2nd day from gestational day (GD) 85 to GD 101. Blood samples were taken from sows repeatedly within 12h after ACTH application on GD 85 and GD 101. On GD 105, fetuses were recovered under general anaesthesia for the collection of blood and brain samples. Plasma cortisol concentrations in sows increased significantly within 2h after ACTH application and returned to control levels after 10h post-application, showing a similar response at the beginning and at the end of the 16-day stimulation period. On GD 101, a significant increase of plasma glucose and insulin concentrations was found in sows after administration of ACTH and after a following feeding time. Number and body weight of fetuses were not affected by the maternal ACTH treatment. Cortisol concentrations in the umbilical vein were significantly decreased in fetuses from ACTH sows and a similar trend was observed in the umbilical artery and in the vena cava cranialis. Glucocorticoid receptor (GR) binding in hippocampus and hypothalamus did not differ between treatments. However, in hippocampus, serotonergic activity was increased in fetuses from ACTH-treated mothers as shown by significantly elevated 5-hydroxytryptamine (5-HT) levels. In conclusion, repeated administrations of ACTH during late gestation resulted in a reproducible cortisol response of sows and reduced cortisol concentrations in the fetal umbilical vein after the treatment period. Although the number of sows used in this experiment was low and differences between treatments were limited these findings indicate that excessive glucocorticoid exposure during gestation alters serotonergic activity in

  1. Blunting of the HPA-axis underlies the lack of preventive efficacy of early post-stressor single-dose Delta-9-tetrahydrocannabinol (THC).

    PubMed

    Mayer, Tzur Alexander; Matar, Michael Alex; Kaplan, Zeev; Zohar, Joseph; Cohen, Hagit

    2014-07-01

    The therapeutic value of Delta-9-tetrahydrocannabinol (Δ9-THC) in the aftermath of trauma has recently raised interest. A prospective animal model for posttraumatic stress disorder was employed to assess the behavioral effects of a single dose of Δ9-THC administered intraperitoneally following exposure to psychogenic stress. Animals were exposed to predator scent stress and treated 1h later with Δ9-THC (1, 5 and 10mg/kg) or vehicle. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 1, 6 and 24 h or 7 days after exposure and freezing behavior upon exposure to a trauma cue on day 8. Pre-set cut-off behavioral criteria classified exposed animals as those with "extreme," "minimal" or "intermediate" (partial) response. Circulating corticosterone levels were assessed over 2h after exposure with and without Δ9-THC. The behavioral effects of a CB1 antagonist (AM251) administered systemically 1h post exposure were evaluated. In the short term (1-6 h), 5 mg/kg of Δ9-THC effectively attenuated anxiety-like behaviors. In the longer-term (7 days), it showed no effect in attenuating PTSD-like behavioral stress responses, or freezing response to trauma cue. Δ9-THC significantly decreased corticosterone levels. In contrast, administration of AM251 (a CB1 antagonist/inverse agonist) 1 h post exposure attenuated long-term behavioral stress responses through activation of the HPA-axis. The demonstrated lack of preventive efficacy of early Δ9-THC treatment and reports of its anxiogenic effects in many individuals raises doubts not only regarding its potential clinical value, but also the advisability of clinical trials. The endocannabinoids exert complex effects on behavioral responses mediating glucocorticoid effects on memory of traumatic experiences.

  2. Adaptation of the hypothalamic-pituitary-adrenal axis and glucose to repeated immobilization or restraint stress is not influenced by associative signals.

    PubMed

    Rabasa, Cristina; Delgado-Morales, Raúl; Muñoz-Abellán, Cristina; Nadal, Roser; Armario, Antonio

    2011-02-01

    Repeated exposure to the same stressor very often results in a reduction of some prototypical stress responses, namely those related to the hypothalamic-pituitary-adrenal (HPA) and sympatho-medullo-adrenal (SMA) axes. This reduced response to repeated exposure to the same (homotypic) stressor (adaptation) is usually considered as a habituation-like process, and therefore, a non-associative type of learning. However, there is some evidence that contextual cues and therefore associative processes could contribute to adaptation. In the present study we demonstrated in two experiments using adult male rats that repeated daily exposure to restraint (REST) or immobilization on boards (IMO) reduced the HPA (plasma levels of ACTH and corticosterone) and glucose responses to the homotypic stressor and such reduced responses remained intact when all putative cues associated to the procedure (experimenter, way of transporting to the stress room, stress boxes, stress room and colour of the restrainer in the case of REST) were modified on the next day. Therefore, the present results do not favour the view that adaptation after repeated exposure to a stressor may involve associative processes related to signals predicting the imminence of the stressors, but more studies are needed on this issue. PMID:20937327

  3. Adrenal insufficiency and adrenal replacement therapy. Current status in Spain.

    PubMed

    Aulinas, Anna; Casanueva, Felipe; Goñi, Fernando; Monereo, Susana; Moreno, Basilio; Picó, Antonio; Puig-Domingo, Manel; Salvador, Javier; Tinahones, Francisco J; Webb, Susan M

    2013-03-01

    Adrenal insufficiency (AI) is a rare endocrine disease, associated to increased mortality if left untreated. It can be due to a primary failure of the adrenal glands (primary AI) or malfunctioning of the hypothalamic-pituitary-adrenal axis (HPA) (secondary AI). The lack of data on incidence/prevalence of adrenal insufficiency in Spain complicates any evaluation of the magnitude of the problem in our country. Initial symptoms are non-specific, so often there is a delay in diagnosis. Current therapy with available glucocorticoids is associated with decreased quality of life in patients with treated AI, as well as with increased mortality and morbidity, probably related to both over-treatment and lack of hydrocortisone, associated with non-physiological peaks and troughs of the drug over the 24 hours. The availability of a new drug with a modified dual release (immediate and retarded), that requires one only daily dose, improves and simplifies the treatment, increases compliance as well as quality of life, morbidity and possibly mortality. This revision deals with the knowledge on the situation both globally and in Spain, prior to the availability of this new drug.

  4. Birth by caesarian section alters postnatal function of the hypothalamic-pituitary-adrenal axis in young pigs.

    PubMed

    Daniel, J A; Keisler, D H; Sterle, J A; Matteri, R L; Carroll, J A

    1999-03-01

    of age. These data indicate that the birth process plays an important role in postnatal function of the hypothalamic-pituitary-adrenal axis in young pigs.

  5. The effect of social stress on adrenal axis activity in horses: the importance of monitoring corticosteroid-binding globulin capacity.

    PubMed

    Alexander, S L; Irvine, C H

    1998-06-01

    Plasma cortisol is largely bound to corticosteroid-binding globulin (CBG), which regulates its bioavailability by restricting exit from capillaries. Levels of CBG may be altered by several factors including stress and this can influence the amount of cortisol reaching cells. This study investigated the effect of social instability on plasma concentrations of CBG, total and free (not protein bound) cortisol in horses. Horses new to our research herd ('newcomers') were confined in a small yard with four dominant resident horses for 3-4 h daily for 3-4 (n = 5) or 9-14 (n = 3) days. Jugular blood was collected in the mornings from newcomers before the period of stress began ('pre-stress'), and then before each day's stress. Residents were bled before stress on the first and thirteenth day. Residents always behaved aggressively towards newcomers. By the end of the stress period, all newcomers were subordinate to residents. In newcomers (n = 8) after 3-4 days of social stress, CBG binding capacity had fallen (P = 0.0025), while free cortisol concentrations had risen (P = 0.0016) from pre-stress values. In contrast, total cortisol did not change. In residents, CBG had decreased slightly but significantly (P = 0.0162) after 12 days of stress. Residents and newcomers did not differ in pre-stress CBG binding capacity, total or free cortisol concentrations. However, by the second week of stress, CBG binding capacity was lower (P = 0.015) and free cortisol higher (P = 0.030) in newcomers (n = 3) than in residents. Total cortisol did not differ between the groups. In conclusion social stress clearly affected the adrenal axis of subordinate newcomer horses, lowering the binding capacity of CBG and raising free cortisol concentrations. However, no effect of stress could be detected when only total cortisol was measured. Therefore, to assess adrenal axis status accurately in horses, it is essential to monitor the binding capacity of CBG and free cortisol concentrations in addition

  6. Gender differences in the long-term effects of chronic prenatal stress on the HPA axis and hypothalamic structure in rats.

    PubMed

    García-Cáceres, Cristina; Lagunas, Natalia; Calmarza-Font, Isabel; Azcoitia, Iñigo; Diz-Chaves, Yolanda; García-Segura, Luis M; Baquedano, Eva; Frago, Laura M; Argente, Jesús; Chowen, Julie A

    2010-11-01

    Stress during pregnancy can impair biological and behavioral responses in the adult offspring and some of these effects are associated with structural changes in specific brain regions. Furthermore, these outcomes can vary according to strain, gender, and type and duration of the maternal stress. Indeed, early stress can induce sexually dimorphic long-term effects on diverse endocrine axes, including subsequent responses to stress. However, whether hypothalamic structural modifications are associated with these endocrine disruptions has not been reported. Thus, we examined the gender differences in the long-term effects of prenatal and adult immobilization stress on the hypothalamic-pituitary-adrenocortical (HPA) axis and the associated changes in hypothalamic structural proteins. Pregnant Wistar rats were subjected to immobilization stress three times daily (45 min each) during the last week of gestation. One half of the offspring were subjected to the same regimen of stress on 10 consecutive days starting at postnatal day (PND) 90. At sacrifice (PND 180), serum corticosterone levels were significantly higher in females compared to males and increased significantly in females subjected to both stresses with no change in males. Prenatal stress increased pituitary ACTH content in males, with no effect in females. Hypothalamic CRH mRNA levels were significantly increased by prenatal stress in females, but decreased in male rats. In females neither stress affected hypothalamic cell death, as determined by cytoplasmic histone-associated DNA fragment levels or proliferation, determined by proliferating cell nuclear antigen levels (PCNA); however, in males there was a significant decrease in cell death in response to prenatal stress and a decrease in PCNA levels with both prenatal and adult stress. In all groups BrdU immunoreactivity colocalized in glial fibrillary acidic protein (GFAP) positive cells, with few BrdU/NeuN labelled cells found. Furthermore, in males the

  7. The hypothalamic-pituitary-adrenal and gonadal axes in rheumatoid arthritis.

    PubMed

    Cutolo, M; Villaggio, B; Foppiani, L; Briata, M; Sulli, A; Pizzorni, C; Faelli, F; Prete, C; Felli, L; Seriolo, B; Giusti, M

    2000-01-01

    The hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes involvement or response to immune activation seems crucial for the control of excessive inflammatory and immune conditions such as autoimmune rheumatic diseases, including rheumatoid arthritis (RA). However, female patients seem to depend more on the HPA axis, whereas male patients seem to depend more on the HPG axis. In particular, hypoandrogenism may play a pathogenetic role in male RA patients because adrenal and gonadal androgens, both products of the HPA and HPG axes, are considered natural immunosuppressors. A significantly altered steroidogenesis of adrenal androgens (i.e., dehydroepiandrosterone sulfate, DHEAS and DHEA) in nonglucocorticoid-treated premenopausal RA patients has been described. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity). A range of physical and psychosocial stressors are also implicated in the activation of the HPA axis and related HPG changes. Chronic and acute stressors appear to have different actions on immune mechanisms with experimental and human studies indicating that acute severe stressors may be even immunosuppressive, while chronic stress may enhance immune responses. The interactions between the immunological and neuroendocrine circuits is the subject of active and extensive ongoing research and might in the near future offer highly promising strategies for hormone-replacement therapies in RA.

  8. Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function

    PubMed Central

    de Vries, Annick; Holmes, Megan C.; Heijnis, Areke; Seier, Jürgen V.; Heerden, Joritha; Louw, Johan; Wolfe-Coote, Sonia; Meaney, Michael J.; Levitt, Naomi S.; Seckl, Jonathan R.

    2007-01-01

    Prenatal stress or glucocorticoid administration has persisting “programming” effects on offspring in rodents and other model species. Multiple doses of glucocorticoids are in widespread use in obstetric practice. To examine the clinical relevance of glucocorticoid programming, we gave 50, 120, or 200 μg/kg/d of dexamethasone (dex50, dex120, or dex200) orally from mid-term to a singleton-bearing nonhuman primate, Chlorocebus aethiops (African vervet). Dexamethasone dose-dependently reduced maternal cortisol levels without effecting maternal blood pressure, glucose, electrolytes, or weight gain. Birth weight was unaffected by any dexamethasone dose, although postnatal growth was attenuated after dex120 and dex200. At 8 months of age, dex120 and dex200 offspring showed impaired glucose tolerance and hyperinsulinemia, with reduced (approximately 25%) pancreatic β cell number at 12 months. Dex120 and dex200 offspring had increased systolic and diastolic blood pressures at 12 months. Mild stress produced an exaggerated cortisol response in dex200 offspring, implying hypothalamic-pituitary-adrenal axis programming. The data are compatible with the extrapolation of the glucocorticoid programming hypothesis to primates and indicate that repeated glucocorticoid therapy and perhaps chronic stress in humans may have long-term effects. PMID:17380204

  9. Hair Cortisol Analysis: A Promising Biomarker of HPA Activation in Older Adults.

    PubMed

    Wright, Kathy D; Hickman, Ronald; Laudenslager, Mark L

    2015-06-01

    Prolonged stress is a potentially harmful and often undetected risk factor for chronic illness in older adults. Cortisol, one indicator of the body's hormonal responses to stress, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and is commonly measured in saliva, urine, or blood samples. Cortisol possesses a diurnal pattern and thus collection timing is critical. Hair cortisol is a proxy measure to the total retrospective activity of the HPA axis over the preceding months, much like hemoglobin A1c is a proxy measure of glucose control over the past 3 months. The aim of this review is to examine a novel biomarker, hair cortisol, as a practical measure of long-term retrospective cortisol activity associated with chronic stress in older adults. Hair cortisol analysis advances the science of aging by better characterizing chronic stress as a risk factor for chronic illness progression and as a biomarker of the effectiveness of stress reduction interventions.

  10. Circadian rise in maternal glucocorticoid prevents pulmonary dysplasia in fetal mice with adrenal insufficiency.

    PubMed

    Venihaki, M; Carrigan, A; Dikkes, P; Majzoub, J A

    2000-06-20

    The hypothalamic-pituitary-adrenal (HPA) axis, including hypothalamic corticotropin-releasing hormone (CRH) and pituitary corticotropin, is one of the first endocrine systems to develop during fetal life, probably because glucocorticoid secretion is necessary for the maturation of many essential fetal organs. Consistent with this, pregnant mice with an inactivating mutation in the Crh gene deliver CRH-deficient offspring that die at birth with dysplastic lungs, which can be prevented by prenatal maternal glucocorticoid treatment. But children lacking the ability to synthesize cortisol (because of various genetic defects in adrenal gland development or steroidogenesis) are not born with respiratory insufficiency or abnormal lung development, suggesting that the transfer of maternal glucocorticoid across the placenta might promote fetal organ maturation in the absence of fetal glucocorticoid production. We used pregnant mice with a normal HPA axis carrying fetuses with CRH deficiency to characterize the relative contributions of the fetal and maternal adrenal to the activity of the fetal HPA axis, and related these findings to fetal lung development. We found that in the presence of fetal adrenal insufficiency, normal fetal lung development is maintained by the transfer of maternal glucocorticoid to the fetus, specifically during the circadian peak in maternal glucocorticoid secretion.

  11. Tuberoinfundibular peptide of 39 residues modulates the mouse hypothalamic-pituitary-adrenal axis via paraventricular glutamatergic neurons.

    PubMed

    Dimitrov, Eugene; Usdin, Ted Björn

    2010-11-01

    Neurons in the subparafascicular area at the caudal border of the thalamus that contain the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) densely innervate several hypothalamic areas, including the paraventricular nucleus (PVN). These areas contain a matching distribution of TIP39's receptor, the parathyroid hormone receptor 2 (PTH2R). Frequent PTH2R coexpression with a vesicular glutamate transporter (VGlut2) suggests that TIP39 could presynaptically regulate glutamate release. By using immunohistochemistry we found CRH-ir neurons surrounded by PTH2R-ir fibers and TIP39-ir axonal projections in the PVN area of the mouse brain. Labeling hypothalamic neuroendocrine neurons by peripheral injection of fluorogold in PTH2R-lacZ knock-in mice showed that most PTH2Rs are on PVN and peri-PVN interneurons and not on neuroendocrine cells. Double fluorescent in situ hybridization revealed a high level of coexpression between PTH2R and VGlut2 mRNA by cells located in the PVN and nearby brain areas. Local TIP39 infusion (100 pmol) robustly increased pCREB-ir in the PVN and adjacent perinuclear zone. It also increased plasma corticosterone and decreased plasma prolactin. These effects of TIP39 on pCREB-ir, corticosterone, and prolactin were abolished by coinfusion of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonopentanoic acid (AP-5; 30 pmol each) and were absent in PTH2R knockout mice. Basal plasma corticosterone was slightly decreased in TIP39 knockout mice just before onset of their active phase. The present data indicate that the TIP39 ligand/PTH2 receptor system provides facilitatory regulation of the hypothalamic-pituitary-adrenal axis via hypothalamic glutamatergic neurons and that it may regulate other neuroendocrine systems by a similar mechanism.

  12. Tuberoinfundibular Peptide of 39 Residues Modulates the Mouse Hypothalamic–Pituitary–Adrenal Axis Via Paraventricular Glutamatergic Neurons

    PubMed Central

    Dimitrov, Eugene; Usdin, Ted Björn

    2010-01-01

    Neurons in the subparafascicular area at the caudal border of the thalamus that contain the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) densely innervate several hypothalamic areas, including the paraventricular nucleus (PVN). These areas contain a matching distribution of TIP39’s receptor, the parathyroid hormone receptor 2 (PTH2R). Frequent PTH2R coexpression with a vesicular glutamate transporter (VGlut2) suggests that TIP39 could presynaptically regulate glutamate release. By using immunohistochemistry we found CRH-ir neurons surrounded by PTH2R-ir fibers and TIP39-ir axonal projections in the PVN area of the mouse brain. Labeling hypothalamic neuroendocrine neurons by peripheral injection of fluorogold in PTH2R-lacZ knock-in mice showed that most PTH2Rs are on PVN and peri-PVN interneurons and not on neuroendocrine cells. Double fluorescent in situ hybridization revealed a high level of coexpression between PTH2R and VGlut2 mRNA by cells located in the PVN and nearby brain areas. Local TIP39 infusion (100 pmol) robustly increased pCREB-ir in the PVN and adjacent perinuclear zone. It also increased plasma corticosterone and decreased plasma prolactin. These effects of TIP39 on pCREB-ir, corticosterone, and prolactin were abolished by coinfusion of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL-2-amino-5-phosphonopentanoic acid (AP-5; 30 pmol each) and were absent in PTH2R knockout mice. Basal plasma corticosterone was slightly decreased in TIP39 knockout mice just before onset of their active phase. The present data indicate that the TIP39 ligand/PTH2 receptor system provides facilitatory regulation of the hypothalamic–pituitary–adrenal axis via hypothalamic glutamatergic neurons and that it may regulate other neuroendocrine systems by a similar mechanism. PMID:20853513

  13. Increased adrenal responsiveness and delayed hatching date in relation to polychlorinated biphenyl exposure in Arctic-breeding black-legged kittiwakes (Rissa tridactyla).

    PubMed

    Tartu, Sabrina; Lendvai, Ádám Z; Blévin, Pierre; Herzke, Dorte; Bustamante, Paco; Moe, Børge; Gabrielsen, Geir Wing; Bustnes, Jan Ove; Chastel, Olivier

    2015-08-01

    High levels of environmental contaminants such as polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and mercury (Hg) have been reported in some Arctic top predators such as seabirds. Chronic exposure to these contaminants might alter the response to environmental changes through interference with the regulation of corticosterone (CORT), a glucocorticoid stress hormone released by the hypothalamo-pituitary-adrenal (HPA) axis. Positive and negative relationships between CORT and environmental contaminants have been reported in polar seabirds. However, patterns appear inconclusive and it is difficult to attribute these relationships to a dysfunction of the HPA axis or to other confounding effects. In order to explore the relationships between the HPA axis activity and contaminants, we tested whether different aspects of the HPA axis of an Arctic seabird, the black-legged kittiwakes Rissa tridactyla, would be related to blood Hg, PCB and OCP concentrations. Male kittiwakes were caught during the incubation period in Svalbard and were subjected to different stress series: (1) a capture-restraint stress protocol, (2) an injection of dexamethasone (DEX) that enabled to test the efficacy of the HPA negative feedback and (3) an injection of adrenocorticotropic hormone (ACTH) that informed on the adrenal responsiveness. The HPA axis activity was unrelated to ΣOCPs and Hg. However, birds with high concentrations of ΣPCBs released more CORT after the ACTH injection. It is suggested that ΣPCBs may increase the number of ACTH-receptors on the adrenals. Additionally, hatching date was delayed in males with higher concentrations of ΣPCBs and ΣOCPs. This study gives new evidence that PCBs and adrenal activity may be related. Thus high PCB burden may make individuals more prone to other stressors such as ongoing climate change.

  14. Sex, Stress, and Mood Disorders: At the Intersection of Adrenal and Gonadal Hormones

    PubMed Central

    Fernández-Guasti, A.; Fiedler, J. L.; Herrera, L.; Handa, R. J.

    2012-01-01

    The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design. PMID:22581646

  15. Stress and the reproductive axis.

    PubMed

    Toufexis, D; Rivarola, M A; Lara, H; Viau, V

    2014-09-01

    There exists a reciprocal relationship between the hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes, wherein the activation of one affects the function of the other and vice versa. For example, both testosterone and oestrogen modulate the response of the HPA axis, whereas activation of the stress axis, especially activation that is repeating or chronic, has an inhibitory effect upon oestrogen and testosterone secretion. Alterations in maternal care can produce significant effects on both HPG and HPA physiology, as well as behaviour in the offspring at adulthood. For example, changes in reproductive behaviour induced by altered maternal care may alter the expression of sex hormone receptors such as oestrogen receptor (ER)α that govern sexual behaviour, and may be particularly important in determining the sexual strategies utilised by females. Stress in adulthood continues to mediate HPG activity in females through activation of a sympathetic neural pathway originating in the hypothalamus and releasing norepinephrine into the ovary, which produces a noncyclic anovulatory ovary that develops cysts. In the opposite direction, sex differences and sex steroid hormones regulate the HPA axis. For example, although serotonin (5-HT) has a stimulatory effect on the HPA axis in humans and rodents that is mediated by the 5-HT1A receptor, only male rodents respond to 5-HT1A antagonism to show increased corticosterone responses to stress. Furthermore, oestrogen appears to decrease 5-HT1A receptor function at presynaptic sites, yet increases 5-HT1A receptor expression at postsynaptic sites. These mechanisms could explain the heightened stress HPA axis responses in females compared to males. Studies on female rhesus macaques show that chronic stress in socially subordinate female monkeys produces a distinct behavioural phenotype that is largely unaffected by oestrogen, a hyporesponsive HPA axis that is hypersensitive to the modulating effects

  16. Stress and the Reproductive Axis

    PubMed Central

    Toufexis, Donna; Rivarola, Maria Angelica; Lara, Hernan; Viau, Victor

    2014-01-01

    There exists a reciprocal relationship between the hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes wherein the activation of one affects the function of the other and vice versa. For instance, both testosterone and oestrogen modulate the response of the HPA axis, while activation of the stress axis, especially activation that is repeating or chronic, has an inhibitory effect upon oestrogen and testosterone secretion. Alterations in maternal care can produce significant effects on both HPG and HPA physiology and behaviour in the offspring at adulthood. For example, changes in reproductive behaviour induced by altered maternal care may alter the expression of sex hormone receptors like ERα that govern sexual behaviour, and may be particularly important in determining the sexual strategies utilized by females. Stress in adulthood continues to mediate HPG activity in females through activation of a sympathetic neural pathway originating in the hypothalamus and releasing norepinephrine (NE) into the ovary, which produces a non-cyclic anovulatory ovary that develops cysts. In the opposite direction, sex differences and sex steroid hormones regulate the HPA axis. For example, although serotonin (5-HT) has a stimulatory effect on the HPA axis in humans and rodents that is mediated by the 5-HT1A receptor, only male rodents respond to 5-HT1A antagonism to show increased corticosterone responses to stress. Furthermore, oestrogen appears to decrease 5-HT1A receptor function at presynaptic sites, yet increase 5-HT1A receptor expression at postsynaptic sites. These mechanisms could explain heightened stress HPA axis responses in females compared to males. Studies on female rhesus macaques show that chronic stress in socially subordinate female monkeys produces a distinct behavioral phenotype that is largely unaffected by oestrogen, a hypo-responsive HPA axis that is hypersensitive to the modulating effects of oestrogen, and changes in 5-HT

  17. Safety assessment of 4'-thio-beta-D-arabinofuranosylcytosine in the beagle dog suggests a drug-induced centrally mediated effect on the hypothalamic-pituitary-adrenal axis.

    PubMed

    Colagiovanni, Dorothy B; Drolet, Daniel W; Dihel, Larry; Meyer, Dennis J; Hart, Karen; Wolf, Julie

    2006-01-01

    4'-Thio-beta-D-arabinofuranosylcytosine (OSI-7836) is a nucleoside analogue with structural similarity to gemcitabine and cytarabine (ara-C). Myelosuppression, reversible transaminase elevations, and flu-like symptoms are common side effects associated with human use of gemcitabine and ara-C. Fatigue is also associated with the use of gemcitabine and OSI-7836 in humans. To better understand the toxicity of OSI-7836, subchronic studies were conducted in dogs. OSI-7836 was administered on days 1 and 8 or on days 1, 2, and 3 of a 21-day dose regimen. These schedules attempted to match clinical trial dosing regimens. Routine toxicity study end points demonstrated that OSI-7836 was primarily cytotoxic to the gastrointestinal tract, bone marrow, and testes; the myelotoxicity was mild and reversible. Plasma pharmacokinetics were dose-linear with an elimination half-life of 2.2 h. Follow-up single dose experiments in dogs assessed drug effects on lymphocyte subpopulations and on adrenal and thyroid function. Populations of T and B cells were equally reduced following OSI-7836 administration. There were no adverse effects on thyroid function, but there were marked reductions in circulating cortisol and adrenocorticotropic hormone concentrations suggesting a centrally mediated impairment of the hypothalamic-pituitary-adrenal axis. These findings show a toxicological profile with OSI-7836 similar to other nucleoside analogues and suggest that the beagle is a model for studying one possible cause of OSI-7836-related fatigue, impaired function of the hypothalamic-pituitary-adrenal axis.

  18. Temporal changes of the adrenal endocrine system in a restraint stressed mouse and possibility of postmortem indicators of prolonged psychological stress.

    PubMed

    Hayashi, Takahito; Ikematsu, Kazuya; Abe, Yuki; Ihama, Yoko; Ago, Kazutoshi; Ago, Mihoko; Miyazaki, Tetsuji; Ogata, Mamoru

    2014-07-01

    We investigated temporal changes of adrenal endocrine systems through the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenomedullary (SA) axis in restraint stressed mice. Restraint stress for 1 day to 3 weeks caused a significant increase in serum levels of ACTH and glucocorticoids accompanied with an increase in adrenal weights, indicating activation of the HPA axis. Reflecting the overproduction of glucocorticoids, adrenal cholesterol content decreased. Moreover, adrenal gene expression involved in cholesterol supply, including scavenger receptor-class B type I, HMG-CoA reductase, and hormone-sensitive lipase, was increased over the same period. After 4 weeks stress, all of these changes returned to control levels. In contrast, adrenal gene expression of chromogranin A, which is cosecreted with catecholamine via the SA axis, was increased with 1 day to 2 weeks of stress, and decreased with 3-4 weeks of stress. Our results suggest that analyses of adrenal endocrine systems based on the combination of several markers examined here would be useful for not only proving prolonged psychological stress experience but also determining its duration.

  19. Loss of melanocortin-4 receptor function attenuates HPA responses to psychological stress.

    PubMed

    Ryan, Karen K; Mul, Joram D; Clemmensen, Christoffer; Egan, Ann E; Begg, Denovan P; Halcomb, Kristen; Seeley, Randy J; Herman, James P; Ulrich-Lai, Yvonne M

    2014-04-01

    The melanocortin 4 receptor (MC4R), well-known for its role in the regulation of energy balance, is widely expressed in stress-regulatory brain regions, including the paraventricular nucleus of the hypothalamus (PVH) and the medial amygdala (MeA). In agreement with this, MC4R has been implicated in hypothalamic-pituitary-adrenocortical axis (HPA) regulation. The present work investigated the role of chronic Mc4r function to modulate basal HPA axis tone and to facilitate acute HPA responses to psychological stress, using a novel rat model with Mc4r loss-of-function. In this study, adult male rats were placed into 3 groups (n=15/group) according to genotype [wild-type (WT); heterozygous mutant (HET); and homozygous mutant (HOM)]. Basal (pre-stress) plasma adrenocorticotropic hormone (ACTH) and corticosterone were measured in the AM and PM, and the HPA axis response to restraint was assessed in the AM. Rats were perfused at 2h after restraint to assess the effect of loss of MC4R on stress-induced c-Fos immunolabeling in stress-regulatory brain regions. We find that basal (non-stress) AM and PM plasma ACTH and corticosterone showed a normal diurnal rhythm that was not altered according to genotype. Consistent with this, adrenal and thymus weights were unaffected by genotype. However, the plasma ACTH and corticosterone responses to restraint were significantly reduced by loss of MC4R function. Likewise, stress-induced c-Fos immunolabeling in both PVH and MeA was significantly reduced by loss of Mc4r function. These results support the hypothesis that endogenous MC4R signaling contributes to the HPA axis response to stress. Because MC4R plays a critical role in the regulation of energy balance, the present work suggests that it may also serve as an important communication link between brain metabolic and stress systems.

  20. Stimulation of the hypothalamo-pituitary-adrenal axis in the rat by three selective type-4 phosphodiesterase inhibitors: in vitro and in vivo studies

    PubMed Central

    Kumari, Meena; Cover, Patricia O; Poyser, Robert H; Buckingham, Julia C

    1997-01-01

    Previous studies in our laboratory have shown that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally or intraperitoneally (i.p.) to adult male rats. This paper describes the results of experiments in which well established in vivo and in vitro methods were used to compare the effects of denbufylline on HPA function with those of two other selective PDE-4 inhibitors, rolipram and BRL 61063 (1,3-dicyclopropylmethyl-8-amino-xanthine). For comparison, parallel measurements of the immunoreactive- (ir-) luteinising hormone (LH) were made where appropriate. When injected intraperitoneally, rolipram (40 and 200 μg kg−1, P<0.005), denbufylline (0.07–0.6 μg kg−1, P<0.05) and BRL 61063 (30 μg kg−1, P<0.005) each produced marked rises in the serum ir-corticosterone concentrations. However, lower doses of rolipram (1.6 and 8 μg kg−1) and BRL 61063 (0.25–6 μg kg−1) were without effect (P>0.05). By contrast, intracerebroventricular (i.c.v.) injection of rolipram (8 ng–1 μg kg−1) or denbufylline (50 ng–1 μg kg−1) failed to influence the serum ir-corticosterone concentration. BRL 61063 (8–120 ng kg−1, i.c.v.) was also ineffective in this regard although at a higher dose (1 μg kg−1, i.c.v.) it produced a small but significant (P<0.05) increase in ir-corticosterone release. Denbufylline also increased the serum ir-LH concentration when given peripherally (0.2–0.6 μg kg−1, i.p., P<0.05) or centrally (100 ng kg−1, i.c.v., P<0.05) but rolipram (1.6–200 μg kg−1, i.p. or 8 ng–1 μg kg−1, i.c.v.) and BRL 61063 (0.25–30 μg kg−1, i.p. or 1 ng–1 μg kg−1, i.c.v.) did not (P>0.05). In vitro rolipram (10 μM, P<0.01), denbufylline (1 mM, P<0.001) and BRL 61063 (1 and 10 μM, P<0.05) stimulated the release of corticotrophin

  1. Adrenal enlargement and failure of suppression of circulating cortisol by dexamethasone in patients with malignancy.

    PubMed

    Jenkins, P J; Sohaib, S A; Trainer, P J; Lister, T A; Besser, G M; Reznek, R

    1999-08-01

    The aim of this study was to further elucidate the activity of the hypothalamo-pituitary-adrenal (HPA) axis in patients with malignancy and to correlate this with the size of the adrenal glands. Fourteen patients with a variety of malignancies were studied prior to receiving cytotoxic chemotherapy. During routine staging computerized tomographic (CT) scans, the size of the body, medial and lateral limbs of the adrenal glands were measured and compared with those of a normal group of patients studied previously. Measurements of 09:00 h serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were made before and after the administration of dexamethasone (0.5 mg 6-hourly for 48 h) in addition to the peak cortisol response to i.v corticotropin releasing hormone (CRH). Overall, patients with malignancy had significantly larger adrenal glands than patients without malignancy; those with non-haematological malignancies had larger glands than patients with haematological malignancies. Following dexamethasone to suppress circulating cortisol levels, nine patients (64%) demonstrated abnormal resistance with cortisol levels > 50 nmol l(-1): mean value 294 nmol l(-1) (range 67-1147). Those patients who failed to suppress after dexamethasone had significantly larger adrenal glands than those that did suppress and tended to have non-haematological malignancies. ACTH levels were undetectable or low in three patients in whom it was measured and who did not suppress with dexamethasone. Following CRH, the cortisol levels were highest (823 and 853 nmol l(-1)) in two of these patients. Malignancy is associated with diffuse enlargement of the adrenal glands and resistance to dexamethasone-induced suppression of the HPA axis, which is not due to ectopic ACTH secretion. This disturbance of the normal control of the HPA axis is unexplained and its functional significance remains uncertain.

  2. HPA function in adolescence: role of sex hormones in its regulation and the enduring consequences of exposure to stressors.

    PubMed

    McCormick, Cheryl M; Mathews, Iva Z

    2007-02-01

    The hypothalamic-pituitary-adrenal (HPA) axis is one of the physiological systems involved in coping with stressors. There are functional shifts in the HPA axis and its regulation by sex hormones over the lifespan that allow the animal to meet the challenges of the internal and external environment that are specific to each stage of development. Sex differences in HPA function emerge over adolescence, a phenomenon reflecting the concomitant initiation of regulatory effects of sex hormones. The focus of this review is recent research on differences between adolescents and adults in HPA function and the enduring effects of exposure to stressors in adolescence. During adolescence, HPA function is characterized by a prolonged activation in response to stressors compared to adulthood, which may render ongoing development of the brain vulnerable. Although research has been scarce, there is a growing evidence that exposure to stressors in adolescence may alter behavioural responses to drugs and cognitive performance in adulthood. However, the effects reported appear to be stressor-specific and sex-specific. Such research may contribute toward understanding the increased risk for drug abuse and psychopathology that occurs over adolescence in people.

  3. Caveats of chronic exogenous corticosterone treatments in adolescent rats and effects on anxiety-like and depressive behavior and hypothalamic-pituitary-adrenal (HPA) axis function

    PubMed Central

    2011-01-01

    Background Administration of exogenous corticosterone is an effective preclinical model of depression, but its use has involved primarily adult rodents. Using two different procedures of administration drawn from the literature, we explored the possibility of exogenous corticosterone models in adolescence, a time of heightened risk for mood disorders in humans. Methods In experiment 1, rats were injected with 40 mg/kg corticosterone or vehicle from postnatal days 30 to 45 and compared with no injection controls on behavior in the elevated plus maze (EPM) and the forced swim test (FST). Experiment 2 consisted of three treatments administered to rats from postnatal days 30 to 45 or as adults (days 70 to 85): either corticosterone (400 μg/ml) administered in the drinking water along with 2.5% ethanol, 2.5% ethanol or water only. In addition to testing on EPM, blood samples after the FST were obtained to measure plasma corticosterone. Analysis of variance (ANOVA) and alpha level of P < 0.05 were used to determine statistical significance. Results In experiment 1, corticosterone treatment of adolescent rats increased anxiety in the EPM and decreased immobility in the FST compared to no injection control rats. However, vehicle injected rats were similar to corticosterone injected rats, suggesting that adolescent rats may be highly vulnerable to stress of injection. In experiment 2, the intake of treated water, and thus doses delivered, differed for adolescents and adults, but there were no effects of treatment on behavior in the EPM or FST. Rats that had ingested corticosterone had reduced corticosterone release after the FST. Ethanol vehicle also affected corticosterone release compared to those ingesting water only, but differently for adolescents than for adults. Conclusions The results indicate that several challenges must be overcome before the exogenous corticosterone model can be used effectively in adolescents. PMID:22738136

  4. Interleukin 1 (IL-1) type I receptors mediate activation of rat hypothalamus-pituitary-adrenal axis and interleukin 6 production as shown by receptor type selective deletion mutants of IL-1beta.

    PubMed

    Van Dam, A M; Malinowsky, D; Lenczowski, M J; Bartfai, T; Tilders, F J

    1998-06-01

    The cytokine interleukin 1 (IL-1) plays an important role in the activation of the hypothalamus-pituary-adrenal (HPA)-axis and interleukin 6 (IL-6) production during infection or inflammation. Which of the interleukin-1 receptor types mediates these effects is not known. To investigate this issue a pharmacological approach was chosen by using recently developed IL-1 receptor type selective ligands. Rats were given one of various doses of recombinant human IL-1beta (rhIL-1beta; 1 and 10 microg/kg) and of several IL-1beta mutants (DeltaSND, DeltaQGE and DeltaI; 1, 10 and 100 microg/kg), that differ in their affinities for the IL-1 type I receptor but have similar affinities for the IL-1 type II receptor. One hour after intravenous administration of rhIL-1beta or IL-1beta mutants, plasma levels of ACTH, corticosterone (cort) and IL-6 were measured. Doses of 1 and 10 microg/kg rhIL-1beta markedly elevated plasma levels of ACTH, cort and IL-6. However, 10-100-fold higher doses of IL-1beta mutants DeltaSND and DeltaQGE and at least 100-fold higher doses of DeltaI have to be administered to increase plasma levels of ACTH, cort and IL-6. The potency differences correlate with their respective affinity for the type I receptor but not with that of the IL-1 type II receptor. It is concluded that IL-1beta induced ACTH, cort and IL-6 production is mediated by interleukin 1 type I receptors.

  5. Modeling of the hypothalamic-pituitary-adrenal axis-mediated interaction between the serotonin regulation pathway and the stress response using a Boolean approximation: a novel study of depression

    PubMed Central

    2013-01-01

    Major depressive disorder (MDD) is a multifactorial disorder known to be influenced by both genetic and environmental factors. MDD presents a heritability of 37%, and a genetic contribution has also been observed in studies of family members of individuals with MDD that imply that the probability of suffering the disorder is approximately three times higher if a first-degree family member is affected. Childhood maltreatment and stressful life events (SLEs) have been established as critical environmental factors that profoundly influence the onset of MDD. The serotonin pathway has been a strong candidate for genetic studies, but it only explains a small proportion of the heritability of the disorder, which implies the involvement of other pathways. The serotonin (5-HT) pathway interacts with the stress response pathway in a manner mediated by the hypothalamic-pituitary-adrenal (HPA) axis. To analyze the interaction between the pathways, we propose the use of a synchronous Boolean network (SBN) approximation. The principal aim of this work was to model the interaction between these pathways, taking into consideration the presence of selective serotonin reuptake inhibitors (SSRIs), in order to observe how the pathways interact and to examine if the system is stable. Additionally, we wanted to study which genes or metabolites have the greatest impact on model stability when knocked out in silico. We observed that the biological model generated predicts steady states (attractors) for each of the different runs performed, thereby proving that the system is stable. These attractors changed in shape, especially when anti-depressive drugs were also included in the simulation. This work also predicted that the genes with the greatest impact on model stability were those involved in the neurotrophin pathway, such as CREB, BDNF (which has been associated with major depressive disorder in a variety of studies) and TRkB, followed by genes and metabolites related to 5-HT

  6. Immunohistochemical analysis of the hypothalamic-pituitary-adrenal axis in dogs: Sex-linked and seasonal variation.

    PubMed

    Gallelli, M F; Lombardo, D; Vissio, P; Quiroga, A; Caggiano, N; Soler, E; Meikle, A; Castillo, V A

    2016-02-01

    This study evaluated sexual dimorphism and seasonal variations in corticotrophs and adrenal zona fasciculata in dogs, as well as the expression of oestrogen receptor alpha (ERα). An immunohistochemical analysis was conducted in pituitaries for ACTH and in adrenal glands for ERα and for the melanocortin-2-receptor (MC2R) in winter and summer. Double immunofluorescence was performed to identify ERα in corticotrophs. Females had a greater proportion of corticotrophs per field (p<0.01), with a greater cellular area and optical density (p<0.001) than males. Optical density of corticotrophs was greater in winter for both sexes (p<0.001). In zona fasciculata, ERα and MC2R expression was greater in females (p<0.001) and was greater in winter (p<0.001). ERα was identified in corticotrophs. This study is the first to demonstrate ERα expression in corticotrophs and the adrenal cortex in dogs, providing evidence for sexual dimorphism and seasonal variations. PMID:26850531

  7. Immunohistochemical analysis of the hypothalamic-pituitary-adrenal axis in dogs: Sex-linked and seasonal variation.

    PubMed

    Gallelli, M F; Lombardo, D; Vissio, P; Quiroga, A; Caggiano, N; Soler, E; Meikle, A; Castillo, V A

    2016-02-01

    This study evaluated sexual dimorphism and seasonal variations in corticotrophs and adrenal zona fasciculata in dogs, as well as the expression of oestrogen receptor alpha (ERα). An immunohistochemical analysis was conducted in pituitaries for ACTH and in adrenal glands for ERα and for the melanocortin-2-receptor (MC2R) in winter and summer. Double immunofluorescence was performed to identify ERα in corticotrophs. Females had a greater proportion of corticotrophs per field (p<0.01), with a greater cellular area and optical density (p<0.001) than males. Optical density of corticotrophs was greater in winter for both sexes (p<0.001). In zona fasciculata, ERα and MC2R expression was greater in females (p<0.001) and was greater in winter (p<0.001). ERα was identified in corticotrophs. This study is the first to demonstrate ERα expression in corticotrophs and the adrenal cortex in dogs, providing evidence for sexual dimorphism and seasonal variations.

  8. GABAergic regulation of the HPA and HPG axes and the impact of stress on reproductive function.

    PubMed

    Camille Melón, Laverne; Maguire, Jamie

    2016-06-01

    The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes are regulated by GABAergic signaling at the level of corticotropin-releasing hormone (CRH) and gonadotropin-releasing hormone (GnRH) neurons, respectively. Under basal conditions, activity of CRH and GnRH neurons are controlled in part by both phasic and tonic GABAergic inhibition, mediated by synaptic and extrasynaptic GABAA receptors (GABAARs), respectively. For CRH neurons, this tonic GABAergic inhibition is mediated by extrasynaptic, δ subunit-containing GABAARs. Similarly, a THIP-sensitive tonic GABAergic current has been shown to regulate GnRH neurons, suggesting a role for δ subunit-containing GABAARs; however, this remains to be explicitly demonstrated. GABAARs incorporating the δ subunit confer neurosteroid sensitivity, suggesting a potential role for neurosteroid modulation in the regulation of the HPA and HPG axes. Thus, stress-derived neurosteroids may contribute to the impact of stress on reproductive function. Interestingly, excitatory actions of GABA have been demonstrated in both CRH neurons at the apex of control of the HPA axis and in GnRH neurons which mediate the HPG axis, adding to the complexity for the role of GABAergic signaling in the regulation of these systems. Here we review the effects that stress has on GnRH neurons and HPG axis function alongside evidence supporting GABAARs as a major interface between the stress and reproductive axes.

  9. GABAergic regulation of the HPA and HPG axes and the impact of stress on reproductive function.

    PubMed

    Camille Melón, Laverne; Maguire, Jamie

    2016-06-01

    The hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes are regulated by GABAergic signaling at the level of corticotropin-releasing hormone (CRH) and gonadotropin-releasing hormone (GnRH) neurons, respectively. Under basal conditions, activity of CRH and GnRH neurons are controlled in part by both phasic and tonic GABAergic inhibition, mediated by synaptic and extrasynaptic GABAA receptors (GABAARs), respectively. For CRH neurons, this tonic GABAergic inhibition is mediated by extrasynaptic, δ subunit-containing GABAARs. Similarly, a THIP-sensitive tonic GABAergic current has been shown to regulate GnRH neurons, suggesting a role for δ subunit-containing GABAARs; however, this remains to be explicitly demonstrated. GABAARs incorporating the δ subunit confer neurosteroid sensitivity, suggesting a potential role for neurosteroid modulation in the regulation of the HPA and HPG axes. Thus, stress-derived neurosteroids may contribute to the impact of stress on reproductive function. Interestingly, excitatory actions of GABA have been demonstrated in both CRH neurons at the apex of control of the HPA axis and in GnRH neurons which mediate the HPG axis, adding to the complexity for the role of GABAergic signaling in the regulation of these systems. Here we review the effects that stress has on GnRH neurons and HPG axis function alongside evidence supporting GABAARs as a major interface between the stress and reproductive axes. PMID:26690789

  10. Adrenal insufficiency: diagnosis and management.

    PubMed

    Munver, Ravi; Volfson, Ilya A

    2006-01-01

    Adrenal insufficiency is a disorder characterized by hypoactive adrenal glands resulting in insufficient production of the hormones cortisol and aldosterone by the adrenal cortex. This disorder may develop as a primary failure of the adrenal cortex or be secondary to an abnormality of the hypothalamic-pituitary axis. Patients with adrenal insufficiency often are asymptomatic or they may present with fatigue, muscle weakness, weight loss, low blood pressure, and sometimes darkening of the skin. The presentation of adrenal insufficiency varies dramatically and poses a major diagnostic dilemma. This review focuses on the diagnosis and treatment of primary and secondary adrenal insufficiency.

  11. The HPA and immune axes in stress: the involvement of the serotonergic system.

    PubMed

    Leonard, B E

    2005-10-01

    The impact of acute and chronic stress on the hypothalamic-pituitary-adrenal (HPA) axis is reviewed and evidence presented that corticotrophin releasing factor (CRF) is the stress neurotransmitter which plays an important role in the activation of the central sympathetic and serotonergic systems. The activity of CRF is expressed through specific receptors (CRF 1 and 2) that are antagonistic in their actions and widely distributed in the limbic regions of the brain, as well as in the hypothalamus, and on immune cells. The mechanism whereby chronic stress, via the CRF induced activation of the dorsal raphe nucleus, can induce a change in the serotonergic system, involves an increase in the 5HT2A and a decrease in the 5HT1A receptor mediated function. Such changes contribute to the onset of anxiety and depression. In addition, the hypersecretion of glucocorticoids that is associated with chronic stress and depression desensitises the central glucocorticoid receptors to the negative feedback inhibition of the HPA axis. This indirectly results in the further activation of the HPA axis. The rise in pro-inflammatory cytokines that usually accompanies the chronic stress response results in a further stimulation of the HPA axis thereby adding to the stress response. While CRF would appear to play a pivotal role, evidence is provided that simultaneous changes in the serotonergic and noradrenergic systems, combined with the activation of peripheral and central macrophages that increase the pro-inflammatory cytokine concentrations in the brain and blood, also play a critical role in predisposing to anxiety and depression. Neurodegenerative changes in the brain that frequently occur in the elderly patient with major depression, could result from the activation of indoleaminedioxygenase (IDO), a widely distributed enzyme that converts tryptophan via the kynenine pathway to for the neurotoxic end product quinolinic acid. PMID:16459240

  12. Exploration of the Hypothalamic-Pituitary-Adrenal Axis to Improve Animal Welfare by Means of Genetic Selection: Lessons from the South African Merino

    PubMed Central

    Hough, Denise; Swart, Pieter; Cloete, Schalk

    2013-01-01

    Simple Summary Breeding sheep that are robust and easily managed may be beneficial for both animal welfare and production. Sheep that are more readily able to adapt to stressful situations and a wide variety of environmental conditions are likely to have more resources available for a higher expression of their production potential. This review explores the utilization of one of the stress response pathways, namely the hypothalamic-pituitary-adrenal axis, to locate potential sites where genetic markers might be identified that contribute to sheep robustness. A South African Merino breeding programme is used to demonstrate the potential benefits of this approach. Abstract It is a difficult task to improve animal production by means of genetic selection, if the environment does not allow full expression of the animal’s genetic potential. This concept may well be the future for animal welfare, because it highlights the need to incorporate traits related to production and robustness, simultaneously, to reach sustainable breeding goals. This review explores the identification of potential genetic markers for robustness within the hypothalamic-pituitary-adrenal axis (HPAA), since this axis plays a vital role in the stress response. If genetic selection for superior HPAA responses to stress is possible, then it ought to be possible to breed robust and easily managed genotypes that might be able to adapt to a wide range of environmental conditions whilst expressing a high production potential. This approach is explored in this review by means of lessons learnt from research on Merino sheep, which were divergently selected for their multiple rearing ability. These two selection lines have shown marked differences in reproduction, production and welfare, which makes this breeding programme ideal to investigate potential genetic markers of robustness. The HPAA function is explored in detail to elucidate where such genetic markers are likely to be found. PMID:26487412

  13. Alterations in hypothalamic-pituitary-adrenal function associated with captivity in Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii).

    PubMed

    Romero, L M; Wingfield, J C

    1999-01-01

    Gambel's white-crowned sparrows were captured and brought into captivity in order to study seasonal changes in the function of the hypothalamic-pituitary-adrenal (HPA) axis in captive birds. 30 min of restraint elicited a rise in corticosterone titers that varied depending upon the season and physiological state of the birds. Restraint elevated corticosterone titers significantly more during the fall (within 2 weeks of capture from the wild) than during either the winter or during a prealternate or prebasic molt. We also examined what changes in the HPA axis could account for altered corticosterone levels. Exogenous ACTH significantly elevated corticosterone levels beyond the response to restraint during the fall, indicating a dramatic enhancement of the adrenal's ability to secrete corticosterone. Exogenous ACTH was ineffective at other times, suggesting that the adrenal's ability to release corticosterone often limits circulating levels. We further inferred the pituitary's ACTH secretory ability by injecting exogenous corticotrophin-releasing factor, arginine vasotocin, and mesotocin and measuring corticosterone release. Pituitaries failed to respond to any exogenous releasing factor during the fall, suggesting that the pituitary may be the site in the HPA axis regulating corticosterone release at this time. When compared to wild-caught birds, these results suggest that captivity alters both adrenal and pituitary function during restraint in white-crowned sparrows, and that this change depends upon the season and/or physiological state of the animal. Captivity thus appears to have a profound affect on the function of the HPA axis, and these results reiterate the caution that must be used to extrapolate laboratory data to field conditions. PMID:10327590

  14. Coupling of the HPA and HPG axes in the context of early life adversity in incarcerated male adolescents.

    PubMed

    Dismukes, Andrew R; Johnson, Megan M; Vitacco, Michael J; Iturri, Florencia; Shirtcliff, Elizabeth A

    2015-09-01

    The effects of early life adversity can be observed across the lifespan, and the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes could be mechanistic intermediaries underlying this phenomenon. The current study examined 50 adolescent males aged 12-18 in a maximum-security correctional and treatment setting. Saliva samples were collected five times a day for 2 days and assayed for cortisol, testosterone, and DHEA. Youth completed semi-structured life stress interviews and self-reports of child maltreatment to index adversity. When youth had higher testosterone levels, they had higher cortisol and DHEA levels, indicating positive "coupling" of the HPA-HPG axes. In addition, children experiencing greater life adversity had tighter coupling of the HPA-HPG axes. Additional analyses hint that coupling may be driven largely by HPG axis functioning. Results indicate that positive coupling of the HPA-HPG axis is observed within incarcerated adolescents, especially for those with the greatest life stress.

  15. No Postoperative Adrenal Insufficiency in a Patient with Unilateral Cortisol-Secreting Adenomas Treated with Mifepristone Before Surgery

    PubMed Central

    Saroka, Rachel M.; Kane, Michael P.; Robinson, Lawrence; Busch, Robert S.

    2016-01-01

    BACKGROUND Glucocorticoid replacement is commonly required to treat secondary adrenal insufficiency after surgical resection of unilateral cortisol-secreting adrenocortical adenomas. Here, we describe a patient with unilateral cortisol-secreting adenomas in which the preoperative use of mifepristone therapy was associated with recovery of the hypothalamic–pituitary–adrenal (HPA) axis, eliminating the need for postoperative glucocorticoid replacement. CASE PRESENTATION A 66-year-old Caucasian man with type 2 diabetes mellitus, hyperlipidemia, hypertension, and obesity was hospitalized for Fournier’s gangrene and methicillin-resistant Staphylococcus aureus sepsis. Abdominal computed tomography scan revealed three left adrenal adenomas measuring 1.4, 2.1, and 1.2 cm and an atrophic right adrenal gland. Twenty-four-hour urinary free cortisol level was elevated (237 µg/24 hours, reference range 0–50 µg/24 hours). Hormonal evaluation after resolution of the infection showed an abnormal 8 mg overnight dexamethasone suppression test (cortisol postdexamethasone 14.5 µg/dL), suppressed adrenocorticotropic hormone (ACTH; <5 pg/mL, reference range 7.2–63.3 pg/mL), and low-normal dehydroepiandrosterone sulfate (50.5 µg/dL, male reference range 30.9–295.6 µg/dL). Because of his poor medical condition and uncontrolled diabetes, his Cushing’s syndrome was treated with medical therapy before surgery. Mifepristone therapy was started and, within five months, his diabetes was controlled and insulin discontinued. The previously suppressed ACTH increased to above normal range accompanied by an increase in dehydroepiandrosterone sulfate levels, indicating recovery of the HPA axis and atrophic contralateral adrenal gland. The patient received one precautionary intraoperative dose of hydrocortisone and none thereafter. Two days postoperatively, ACTH (843 pg/mL) and cortisol levels (44.8 µg/dL) were significantly elevated, reflecting an appropriate HPA axis response to

  16. Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress

    NASA Technical Reports Server (NTRS)

    Meerlo, P.; Koehl, M.; van der Borght, K.; Turek, F. W.

    2002-01-01

    Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short-lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8-day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30-min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under

  17. Prevention of 5-hydroxytryptamine2C receptor RNA editing and alternate splicing in C57BL/6 mice activates the hypothalamic-pituitary-adrenal axis and alters mood

    PubMed Central

    Bombail, Vincent; Qing, Wei; Chapman, Karen E; Holmes, Megan C

    2014-01-01

    The 5-hydroxytryptamine2C (5-HT)2C receptor is widely implicated in the aetiology of affective and eating disorders as well as regulation of the hypothalamo-pituitary-adrenal axis. Signalling through this receptor is regulated by A-to-I RNA editing, affecting three amino acids in the protein sequence, with unedited transcripts encoding a receptor (INI) that, in vitro, is hyperactive compared with edited isoforms. Targeted alteration (knock-in) of the Htr2c gene to generate ‘INI’ mice with no alternate splicing, solely expressing the full-length unedited isoform, did not produce an overt metabolic phenotype or altered anxiety behaviour, but did display reduced depressive-like and fear-associated behaviours. INI mice exhibited a hyperactive hypothalamo-pituitary-adrenal axis, with increased nadir plasma corticosterone and corticotrophin-releasing hormone expression in the hypothalamus but responded normally to chronic stress and showed normal circadian activity and activity in a novel environment. The circadian patterns of 5-HT2C receptor mRNA and mbii52, a snoRNA known to regulate RNA editing and RNA splicing of 5-HT2C receptor pre-mRNA, were altered in INI mice compared with wild-type control mice. Moreover, levels of 5-HT1A receptor mRNA were increased in the hippocampus of INI mice. These gene expression changes may underpin the neuroendocrine and behavioural changes observed in INI mice. However, the phenotype of INI mice was not consistent with a globally hyperactive INI receptor encoded by the unedited transcript in the absence of alternate splicing. Hence, the in vivo outcome of RNA editing may be neuronal cell type specific. PMID:25257581

  18. Does aerobic exercise affect the hypothalamic-pituitary-adrenal hormonal response in patients with fibromyalgia syndrome?

    PubMed Central

    Genc, Aysun; Tur, Birkan Sonel; Aytur, Yesim Kurtais; Oztuna, Derya; Erdogan, Murat Faik

    2015-01-01

    [Purpose] The hypothalamic-pituitary-adrenal (HPA) axis in the etiopathogenesis of fibromyalgia is not clear. This study aimed to analyze the effects of a 6-week aerobic exercise program on the HPA axis in patients with fibromyalgia and to investigate the effects of this program on the disease symptoms, patients’ fitness, disability, and quality of life. [Subjects and Methods] Fifty fibromyalgia patients were randomized to Group 1 (stretching and flexibility exercises at home for 6 weeks) and Group 2 (aerobic exercise three times a week and the same at-home exercises as Group 1 for 6 weeks). Serum levels of cortisol, adrenocorticotropic hormone, insulin-like growth factor-1, and growth hormone were analyzed at baseline and at the end of, and 1 hr after an exercise stress test. [Results] Group 2 showed better improvement in morning stiffness duration and pain. Growth hormone levels significantly increased after intervention and cortisol levels significantly decreased at time-time interaction in both groups. No significant differences in adrenocorticotropic hormone and insulin-like growth factor-1 were found. [Conclusion] The results of this study seem to support the hypothesis that there is a dysregulation of the HPA axis in patients with FM, and that a six-week exercise program can influence symptoms and affect the HPA axis hormones. PMID:26311959

  19. HPA Axis Gene Expression and DNA Methylation Profiles in Rats Exposed to Early Life Stress, Adult Voluntary Ethanol Drinking and Single Housing

    PubMed Central

    Todkar, Aniruddha; Granholm, Linnea; Aljumah, Mujtaba; Nilsson, Kent W.; Comasco, Erika; Nylander, Ingrid

    2016-01-01

    The neurobiological basis of early life stress (ELS) impact on vulnerability to alcohol use disorder is not fully understood. The effect of ELS, adult ethanol consumption and single housing, on expression of stress and DNA methylation regulatory genes as well as blood corticosterone levels was investigated in the hypothalamus and pituitary of adult out-bred Wistar rats subjected to different rearing conditions. A prolonged maternal separation (MS) of 360 min (MS360) was used to study the effect of ELS, and a short MS of 15 min (MS15) was used as a control. Voluntary ethanol drinking was assessed using a two-bottle free choice paradigm to simulate human episodic drinking. The effects of single housing and ethanol were assessed in conventional animal facility rearing (AFR) conditions. Single housing in adulthood was associated with lower Crhr1 and higher Pomc expression in the pituitary, whereas ethanol drinking was associated with higher expression of Crh in the hypothalamus and Crhr1 in the pituitary, accompanied by lower corticosterone levels. As compared to controls with similar early life handling, rats exposed to ELS displayed lower expression of Pomc in the hypothalamus, and higher Dnmt1 expression in the pituitary. Voluntary ethanol drinking resulted in lower Fkbp5 expression in the pituitary and higher Crh expression in the hypothalamus, independently of rearing conditions. In rats exposed to ELS, water and ethanol drinking was associated with higher and lower corticosterone levels, respectively. The use of conventionally reared rats as control group yielded more significant results than the use of rats exposed to short MS. Positive correlations, restricted to the hypothalamus and ELS group, were observed between the expression of the hypothalamus-pituitary-adrenal receptor and the methylation-related genes. Promoter DNA methylation and expression of respective genes did not correlate suggesting that other loci are involved in transcriptional regulation

  20. Reducing treatments in cattle superovulation protocols by combining a pituitary extract with a 5% hyaluronan solution: Is it able to diminish activation of the hypothalamic pituitary adrenal axis compared to the traditional protocol?

    PubMed

    Biancucci, Andrea; Sbaragli, Tatiana; Comin, Antonella; Sylla, Lakamy; Monaci, Maurizio; Peric, Tanja; Stradaioli, Giuseppe

    2016-03-15

    Traditional superovulation protocols that include multiple gonadotropin treatments are time-consuming and labor intensive. These protocols require multiple handling and restraining of embryo donors. This will likely increase the risks of injuries in both animals and humans and induce stress that may lead to a reduced superovulatory response. These are more evident when working with cattle that are rarely handled or raised on extensive grazing. The objectives of this experiment were to compare the efficacy of a split-injection protocol of porcine pituitary-derived porcine FSH (pFSH) preparation (slow release [SR] group) to the traditional 4-day treatment with pFSH administered twice daily (C group) and to determine the concentrations of cortisol in the hair as a marker of activation of the hypothalamic-pituitary-adrenal (HPA) axis during the two superovulatory treatments. Thirty-two heifers were stimulated twice in a 2 × 2 crossover design and compared for ovarian response and numbers and characteristics of recovered ova-embryo among treatments. No differences between SR and C groups were found in terms of percentage of responsive animals (100% vs. 93.8%) and ovulation rate (83.7 ± 1.1 vs. 79.5 ± 1.0%). A positive correlation was found between the number of follicles responsive to pFSH (2-8 mm) at the beginning of treatments and the superovulatory response, and no differences were found in these follicular populations between the two treatment groups. The numbers of CLs, ova-embryos, fertilized ova, transferable and freezable embryos recovered per cow were found to be significantly higher in SR compared with C group (14.0 ± 1.6 vs. 10.6 ± 1.0, 12.1 ± 1.6 vs. 7.6 ± 1.0, 11.1 ± 1.1 vs. 7.3 ± 1.0, 9.6 ± 1.4 vs. 6.6 ± 1.0, and 9.4 ± 1.4 vs. 6.0 ± 1.0 for SR and C group, respectively). The SR group produced also a significantly greater number of excellent- and/or good-quality embryos compared with the C group. The concentrations of cortisol in the hair at

  1. Reducing treatments in cattle superovulation protocols by combining a pituitary extract with a 5% hyaluronan solution: Is it able to diminish activation of the hypothalamic pituitary adrenal axis compared to the traditional protocol?

    PubMed

    Biancucci, Andrea; Sbaragli, Tatiana; Comin, Antonella; Sylla, Lakamy; Monaci, Maurizio; Peric, Tanja; Stradaioli, Giuseppe

    2016-03-15

    Traditional superovulation protocols that include multiple gonadotropin treatments are time-consuming and labor intensive. These protocols require multiple handling and restraining of embryo donors. This will likely increase the risks of injuries in both animals and humans and induce stress that may lead to a reduced superovulatory response. These are more evident when working with cattle that are rarely handled or raised on extensive grazing. The objectives of this experiment were to compare the efficacy of a split-injection protocol of porcine pituitary-derived porcine FSH (pFSH) preparation (slow release [SR] group) to the traditional 4-day treatment with pFSH administered twice daily (C group) and to determine the concentrations of cortisol in the hair as a marker of activation of the hypothalamic-pituitary-adrenal (HPA) axis during the two superovulatory treatments. Thirty-two heifers were stimulated twice in a 2 × 2 crossover design and compared for ovarian response and numbers and characteristics of recovered ova-embryo among treatments. No differences between SR and C groups were found in terms of percentage of responsive animals (100% vs. 93.8%) and ovulation rate (83.7 ± 1.1 vs. 79.5 ± 1.0%). A positive correlation was found between the number of follicles responsive to pFSH (2-8 mm) at the beginning of treatments and the superovulatory response, and no differences were found in these follicular populations between the two treatment groups. The numbers of CLs, ova-embryos, fertilized ova, transferable and freezable embryos recovered per cow were found to be significantly higher in SR compared with C group (14.0 ± 1.6 vs. 10.6 ± 1.0, 12.1 ± 1.6 vs. 7.6 ± 1.0, 11.1 ± 1.1 vs. 7.3 ± 1.0, 9.6 ± 1.4 vs. 6.6 ± 1.0, and 9.4 ± 1.4 vs. 6.0 ± 1.0 for SR and C group, respectively). The SR group produced also a significantly greater number of excellent- and/or good-quality embryos compared with the C group. The concentrations of cortisol in the hair at

  2. Adrenal Insufficiency

    MedlinePlus

    ... What is adrenal insufficiency? Did you know? The adrenal glands, located on top of the kidneys, make hormones ... body functions. The outer layer (cortex) of the adrenal glands makes three types of steroid hormones. In adrenal ...

  3. Modeling the involvement of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes in autoimmune and stress-related rheumatic syndromes in women.

    PubMed

    Crofford, L J; Jacobson, J; Young, E

    1999-03-01

    Autoimmune and stress-related rheumatic diseases are significantly more common in women than in men. Our group has focused on the role of two principal neuroendocrine axes, the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis, in this increased susceptibility to rheumatic disease. We review the physiology of the HPA and HPG axes and discuss their reciprocal interactions. Mechanisms by which hormones of the HPA and HPG axes influence the immune system and modulate the course of autoimmune inflammatory diseases in animal models of rheumatic disease are described. In addition, we review the data suggesting the importance of these neurohormonal systems in rheumatic diseases. These data provide insights into why women may be at increased risk and how we might better understand the mechanisms that provoke expression of rheumatic diseases in women. To advance research in this area, it is critical to develop methods to evaluate the function of the neuroendocrine axes. Secretion of both HPA and HPG axis hormones, particularly the hormones of the hypothalamus and anterior pituitary, is largely by intermittent pulses. In addition, the HPA axis exhibits a profound circadian, or near 24-hour, variation, and HPG axis hormones fluctuate over the monthly cycle. These factors make meaningful analysis of these axes quite complex. We discuss models used in the analyses of neuroendocrine axes and the use of challenge testing to assess the integrity of neuroendocrine axes.

  4. Megace Mystery: A Case of Central Adrenal Insufficiency

    PubMed Central

    Mehta, Kunal; Weiss, Irene; Goldberg, Michael D.

    2015-01-01

    Megestrol acetate (MA) is a synthetic progestin with both antineoplastic and orexigenic properties. In addition to its effects on the progesterone receptor, MA also binds the glucocorticoid receptor. Some patients receiving MA therapy have been reported to develop clinical features of glucocorticoid excess, while others have experienced the clinical syndrome of cortisol deficiency—either following withdrawal of MA therapy or during active treatment. We describe a patient who presented with clinical and biochemical features of central adrenal insufficiency. Pituitary function was otherwise essentially normal, and the etiology of the isolated ACTH suppression was initially unclear. The use of an exogenous glucocorticoid was suspected but was initially denied by the patient; ultimately, the culprit medication was uncovered when a synthetic steroid screen revealed the presence of MA. The patient's symptoms improved after she was switched to hydrocortisone. Clinicians should be aware of the potential effects of MA on the hypothalamic-pituitary-adrenal (HPA) axis. PMID:26770843

  5. Functional Connections of the Vestibulo-spino-adrenal Axis in the Control of Blood Pressure Via the Vestibulosympathetic Reflex in Conscious Rats

    PubMed Central

    Lu, Huan-Jun; Li, Mei-Han; Li, Mei-Zhi; Park, Sang Eon; Kim, Min Sun

    2015-01-01

    Significant evidence supports the role of the vestibular system in the regulation of blood pressure during postural movements. In the present study, the role of the vestibulo-spino-adrenal (VSA) axis in the modulation of blood pressure via the vestibulosympathetic reflex was clarified by immunohistochemical and enzyme immunoassay methods in conscious rats with sinoaortic denervation. Expression of c-Fos protein in the intermediolateral cell column of the middle thoracic spinal regions and blood epinephrine levels were investigated, following microinjection of glutamate receptor agonists or antagonists into the medial vestibular nucleus (MVN) and/or sodium nitroprusside (SNP)-induced hypotension. Both microinjection of glutamate receptor agonists (NMDA and AMPA) into the MVN or rostral ventrolateral medullary nucleus (RVLM) and SNP-induced hypotension led to increased number of c-Fos positive neurons in the intermediolateral cell column of the middle thoracic spinal regions and increased blood epinephrine levels. Pretreatment with microinjection of glutamate receptor antagonists (MK-801 and CNQX) into the MVN or RVLM prevented the increased number of c-Fos positive neurons resulting from SNP-induced hypotension, and reversed the increased blood epinephrine levels. These results indicate that the VSA axis may be a key component of the pathway used by the vestibulosympathetic reflex to maintain blood pressure during postural movements. PMID:26330755

  6. Expression of adiponectin receptors in mouse adrenal glands and the adrenocortical Y-1 cell line: adiponectin regulates steroidogenesis.

    PubMed

    Li, Ping; Sun, Fei; Cao, Huang-Ming; Ma, Qin-Yun; Pan, Chun-Ming; Ma, Jun-Hua; Zhang, Xiao-Na; Jiang, He; Song, Huai-Dong; Chen, Ming-Dao

    2009-12-25

    Obesity is frequently associated with malfunctions of the hypothalamus-pituitary-adrenal (HPA) axis and hyperaldosteronism, but the mechanism underlying this association remains unclear. Since the adrenal glands are embedded in adipose tissue, direct cross-talk between adipose tissue and the adrenal gland has been proposed. A previous study found that adiponectin receptor mRNA was expressed in human adrenal glands and aldosterone-producing adenoma (APA). However, the expression of adiponectin receptors in adrenal glands has not been confirmed at the protein level or in other species. Furthermore, it is unclear whether adiponectin receptors expressed in adrenal cells are functional. We found, for the first time, that adiponectin receptor (AdipoR1 and AdipoR2) mRNA and protein were expressed in mouse adrenal and adrenocortical Y-1 cells. However, adiponectin itself was not expressed in mouse adrenal or Y-1 cells. Furthermore, adiponectin acutely reduced basal levels of corticosterone and aldosterone secretion. ACTH-induced steroid secretion was also inhibited by adiponectin, and this was accompanied by a parallel change in the expression of the key genes involved in steroidogenesis. These findings indicate that adiponectin may take part in the modulation of steroidogenesis. Thus, adiponectin is likely to have physiological and/or pathophysiological significance as an endocrine regulator of adrenocortical function.

  7. The phosphodiesterases type 5 inhibitor tadalafil reduces the activation of the hypothalamus-pituitary-adrenal axis in men during cycle ergometric exercise.

    PubMed

    Di Luigi, Luigi; Sgrò, Paolo; Baldari, Carlo; Gallotta, Maria Chiara; Emerenziani, Gian Pietro; Crescioli, Clara; Bianchini, Serena; Romanelli, Francesco; Lenzi, Andrea; Guidetti, Laura

    2012-04-15

    Phosphodiesterase type 5 inhibitors may influence human physiology, health, and performance by also modulating endocrine pathways. We evaluated the effects of a 2-day tadalafil administration on adenohypophyseal and adrenal hormone adaptation to exercise in humans. Fourteen healthy males were included in a double-blind crossover trial. Each volunteer randomly received two tablets of placebo or tadalafil (20 mg/day with a 36-h interval) before a maximal exercise was performed. After a 2-wk washout, the volunteers were crossed over. Blood samples were collected at -30 and -15 min and immediately before exercise, immediately after, and during recovery (+15, +30, +60, and +90 min) for adrenocorticotropin (ACTH), β-endorphin, growth hormone (GH), prolactin, cortisol (C), corticosterone, dehydroepiandrosterone-sulfate (DHEAS), and cortisol binding globulin (CBG) assays. C-to-CBG (free cortisol index, FCI) and DHEAS-to-C ratios were calculated. Exercise intensity, perceived exertion rate, O₂ consumption, and CO₂ and blood lactate concentration were evaluated. ACTH, GH, C, corticosterone, and CBG absolute concentrations and/or areas under the curve (AUC) increased after exercise after both placebo and tadalafil. Exercise increased DHEAS only after placebo. Compared with placebo, tadalafil administration reduced the ACTH, C, corticosterone, and FCI responses to exercise and was associated with higher β-endorphin AUC and DHEAS-to-C ratio during recovery, without influencing cardiorespiratory and performance parameters. Tadalafil reduced the activation of the hypothalamus-pituitary-adrenal axis during exercise by probably influencing the brain's nitric oxide- and cGMP-mediated pathways. Further studies are necessary to confirm our results and to identify the involved mechanisms, possible health risks, and potential clinical uses.

  8. Variation in the ovine cortisol response to systemic bacterial endotoxin challenge is predominantly determined by signalling within the hypothalamic-pituitary-adrenal axis

    SciTech Connect

    You Qiumei; Karrow, Niel A. Cao Honghe; Rodriguez, Alexander; Mallard, Bonnie A.; Boermans, Herman J.

    2008-07-01

    Bi-directional communication between the neuroendocrine and immune systems is designed, in part, to maintain or restore homeostasis during physiological stress. Exposure to endotoxin during Gram-negative bacterial infection for example, elicits the release of pro-inflammatory cytokines that activate the hypothalamic-pituitary-adrenal axis (HPAA). The secretion of adrenal glucocorticoids subsequently down regulates the host inflammatory response, minimizing potential tissue damage. Sequence and epigenetic variants in genes involved in regulating the neuroendocrine and immune systems are likely to contribute to individual differences in the HPAA response, and this may influence the host anti-inflammatory response to toxin exposure and susceptibility to inflammatory disease. In this study, high (HCR) and low (LCR) cortisol responders were selected from a normal population of 110 female sheep challenged iv with Escherichia coli endotoxin (400 ng/kg) to identify potential determinants that contribute to variation in the cortisol response phenotype. This phenotype was stable over several years in the HCR and LCR animals, and did not appear to be attributed to differences in expression of hepatic immune-related genes or systemic pro-inflammatory cytokine concentrations. Mechanistic studies using corticotrophin-releasing factor (0.5 {mu}g/kg body weight), arginine vasopressin (0.5 {mu}g/kg), and adrenocorticotropic hormone (0.5 {mu}g/kg) administered iv demonstrated that variation in this phenotype is largely determined by signalling within the HPAA. Future studies will use this ovine HCR/LCR model to investigate potential genetic and epigenetic variants that may contribute to variation in cortisol responsiveness to bacterial endotoxin.

  9. Temperament and hypothalamic-pituitary-adrenal axis function are related and combine to affect growth, efficiency, carcass, and meat quality traits in Brahman steers.

    PubMed

    Cafe, L M; Robinson, D L; Ferguson, D M; Geesink, G H; Greenwood, P L

    2011-05-01

    analysis separated these traits into separate components, which in turn had different relations with productivity traits. The largest component of temperament was described similarly by FS and CS, but there were smaller components that these described differently. There were some temperament-related differences in the metabolic status of the steers which were not related to the variation in cortisol, suggesting involvement of the sympatho-adrenal-medullary axis in these temperament-related effects. PMID:21414739

  10. Temperament and hypothalamic-pituitary-adrenal axis function are related and combine to affect growth, efficiency, carcass, and meat quality traits in Brahman steers.

    PubMed

    Cafe, L M; Robinson, D L; Ferguson, D M; Geesink, G H; Greenwood, P L

    2011-05-01

    analysis separated these traits into separate components, which in turn had different relations with productivity traits. The largest component of temperament was described similarly by FS and CS, but there were smaller components that these described differently. There were some temperament-related differences in the metabolic status of the steers which were not related to the variation in cortisol, suggesting involvement of the sympatho-adrenal-medullary axis in these temperament-related effects.

  11. Reunion behavior after social separation is associated with enhanced HPA recovery in young marmoset monkeys.

    PubMed

    Taylor, Jack H; Mustoe, Aaryn C; Hochfelder, Benjamin; French, Jeffrey A

    2015-07-01

    The relationships that offspring develop with caregivers can exert a powerful influence on behavior and physiology, including the hypothalamic-pituitary-adrenal (HPA) axis. In many mammalian species, offspring-caregiver relationships are largely limited to interactions with mother. Marmoset monkeys receive care in early life from multiple classes of caregivers in addition to the mother, including fathers and siblings. We evaluated whether affiliative social interactions with family members in marmosets were associated with differences in cortisol reactivity to a short-term social separation stressor, and whether these variations in affiliative interactions upon reunion predicted how well marmosets subsequently regulated HPA axis function after cessation of the stressor. Marmosets were separated from the family for 8h at three developmental time points (6-, 12-, and 18-months of age), and interactions of the separated marmoset with the family group were recorded during reunion. Urinary cortisol was measured prior to social separation, every 2h during the separation, and on the morning after separation. Heightened cortisol reactivity during social separation did not predict affiliative social behavior upon reunion but higher rates of grooming and play behavior predicted enhanced HPA regulation. Marmosets with higher rates of grooming and play with family members upon reunion had post-stress cortisol levels closer to preseparation baseline than marmosets with lower rates of affiliative reunion behavior. Combined with previous research showing the early programming effects of social interactions with caregivers, as well as the buffering effect of a close social partner during stress, the current study highlights the high degree of behavioral and HPA adaptability to social stressors across development in marmoset monkeys. PMID:25900596

  12. Reunion behavior after social separation is associated with enhanced HPA recovery in young marmoset monkeys.

    PubMed

    Taylor, Jack H; Mustoe, Aaryn C; Hochfelder, Benjamin; French, Jeffrey A

    2015-07-01

    The relationships that offspring develop with caregivers can exert a powerful influence on behavior and physiology, including the hypothalamic-pituitary-adrenal (HPA) axis. In many mammalian species, offspring-caregiver relationships are largely limited to interactions with mother. Marmoset monkeys receive care in early life from multiple classes of caregivers in addition to the mother, including fathers and siblings. We evaluated whether affiliative social interactions with family members in marmosets were associated with differences in cortisol reactivity to a short-term social separation stressor, and whether these variations in affiliative interactions upon reunion predicted how well marmosets subsequently regulated HPA axis function after cessation of the stressor. Marmosets were separated from the family for 8h at three developmental time points (6-, 12-, and 18-months of age), and interactions of the separated marmoset with the family group were recorded during reunion. Urinary cortisol was measured prior to social separation, every 2h during the separation, and on the morning after separation. Heightened cortisol reactivity during social separation did not predict affiliative social behavior upon reunion but higher rates of grooming and play behavior predicted enhanced HPA regulation. Marmosets with higher rates of grooming and play with family members upon reunion had post-stress cortisol levels closer to preseparation baseline than marmosets with lower rates of affiliative reunion behavior. Combined with previous research showing the early programming effects of social interactions with caregivers, as well as the buffering effect of a close social partner during stress, the current study highlights the high degree of behavioral and HPA adaptability to social stressors across development in marmoset monkeys.

  13. Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis.

    PubMed

    Droste, Susanne K; Gesing, Angela; Ulbricht, Sabine; Müller, Marianne B; Linthorst, Astrid C E; Reul, Johannes M H M

    2003-07-01

    We studied the effects of long-term (i.e. 4 wk) voluntary exercise on the hypothalamic-pituitary-adrenocortical (HPA) axis in male mice. Voluntary exercise was provided by giving mice access to a running wheel, in which they indeed ran for about 4 km/d. Exercising mice showed similar body weights as control animals but presented less abdominal fat, lighter thymuses, and heavier adrenal glands. Exercise resulted in asymmetric structural changes in the adrenal glands. Whereas control mice had larger left than right adrenals, this condition was abolished in exercising animals, mainly because of enlargement of the right adrenal cortex. Tyrosine hydroxylase mRNA expression in the adrenal medullas of exercising mice was increased. In exercising mice, early-morning baseline plasma ACTH levels were decreased, whereas plasma corticosterone levels at the start of the dark phase were twice as high as those in control animals. To forced swimming and restraint stress, exercising mice responded with higher corticosterone levels than those of the control animals but with similar ACTH levels. However, if exposed to a novel environment, then exercising mice presented decreased ACTH responses. Interestingly, exercising mice showed a decreased corticosterone response to novelty only when the novel environment contained a functioning running wheel. Glucocorticoid receptor levels were unchanged, whereas mineralocorticoid receptor levels were decreased, in hippocampus of exercising animals. Corticotropin-releasing factor mRNA levels in the paraventricular nucleus were lower in exercising mice. Thus, voluntary exercise results in complex, adaptive changes at various levels within the HPA axis as well as in sympathoadrenomedullary and limbic/neocortical afferent control mechanisms. These changes seem to underlie the differential responsiveness of the HPA axis to physical vs. emotional challenges.

  14. Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis.

    PubMed

    Droste, Susanne K; Gesing, Angela; Ulbricht, Sabine; Müller, Marianne B; Linthorst, Astrid C E; Reul, Johannes M H M

    2003-07-01

    We studied the effects of long-term (i.e. 4 wk) voluntary exercise on the hypothalamic-pituitary-adrenocortical (HPA) axis in male mice. Voluntary exercise was provided by giving mice access to a running wheel, in which they indeed ran for about 4 km/d. Exercising mice showed similar body weights as control animals but presented less abdominal fat, lighter thymuses, and heavier adrenal glands. Exercise resulted in asymmetric structural changes in the adrenal glands. Whereas control mice had larger left than right adrenals, this condition was abolished in exercising animals, mainly because of enlargement of the right adrenal cortex. Tyrosine hydroxylase mRNA expression in the adrenal medullas of exercising mice was increased. In exercising mice, early-morning baseline plasma ACTH levels were decreased, whereas plasma corticosterone levels at the start of the dark phase were twice as high as those in control animals. To forced swimming and restraint stress, exercising mice responded with higher corticosterone levels than those of the control animals but with similar ACTH levels. However, if exposed to a novel environment, then exercising mice presented decreased ACTH responses. Interestingly, exercising mice showed a decreased corticosterone response to novelty only when the novel environment contained a functioning running wheel. Glucocorticoid receptor levels were unchanged, whereas mineralocorticoid receptor levels were decreased, in hippocampus of exercising animals. Corticotropin-releasing factor mRNA levels in the paraventricular nucleus were lower in exercising mice. Thus, voluntary exercise results in complex, adaptive changes at various levels within the HPA axis as well as in sympathoadrenomedullary and limbic/neocortical afferent control mechanisms. These changes seem to underlie the differential responsiveness of the HPA axis to physical vs. emotional challenges. PMID:12810557

  15. Replacement therapy with DHEA plus corticosteroids in patients with chronic inflammatory diseases--substitutes of adrenal and sex hormones.

    PubMed

    Straub, R H; Schölmerich, J; Zietz, B

    2000-01-01

    A dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis was found in animal models of chronic inflammatory diseases, and the defect was located in more central portions of the HPA axis. This defect of neuroendocrine regulatory mechanisms contributes to the onset of the model disease. Since these first observations in animal models were made, evidence has accumulated that the possible defect in the HPA axis in humans is more distal to the hypothalamus or pituitary gland: In chronic inflammatory diseases, such as rheumatoid arthritis, an alteration of the HPA stress response results in inappropriately low cortisol secretion in relation to adrenocorticotropic hormone (ACTH) secretion. Furthermore, it has recently been shown that the serum levels of another adrenal hormone, dehydroepiandrosterone (DHEA), were significantly lower after ACTH stimulation in patients with rheumatoid arthritis without prior corticosteroids than in healthy controls. These studies clearly indicate that chronic inflammation alters, particularly, the adrenal response. However, at this point, the reason for the specific alteration of adrenal function in relation to pituitary function remains to be determined. Since one of the down-regulated adrenal hormones, DHEA, is an inhibitor of cytokines due to an inhibition of nuclear factor-kappa B (NF-kappa B) activation, low levels of this hormone may be deleterious in chronic inflammatory diseases. We have recently demonstrated that DHEA is a potent inhibitor of IL-6, which confirmed an earlier study in mice. Since IL-6 is an important factor for B lymphocyte differentiation, the missing down-regulation of this cytokine, and others such as TNF, may be a significant risk factor in rheumatic diseases. Since in these patients, administration of prednisolone or the chronic inflammatory process itself alters adrenal function, endogenous adrenal hormones in relation to proinflammatory cytokines change. Furthermore, these mechanisms may also lead to

  16. Epidemiological support for genetic variability at hypothalamic–pituitary–adrenal axis and serotonergic system as risk factors for major depression

    PubMed Central

    Ching-López, Ana; Cervilla, Jorge; Rivera, Margarita; Molina, Esther; McKenney, Kathryn; Ruiz-Perez, Isabel; Rodríguez-Barranco, Miguel; Gutiérrez, Blanca

    2015-01-01

    support the notion that the hypothalamic–pituitary–adrenal and serotonergic systems are likely to be involved in the genetic susceptibility for MDD. Future studies, including larger samples, should be addressed for further validation and replication of the present findings. PMID:26543368

  17. Pilot study of adrenal steroid hormones in hair as an indicator of chronic mental and physical stress.

    PubMed

    Ullmann, E; Barthel, A; Petrowski, K; Stalder, T; Kirschbaum, C; Bornstein, S R

    2016-01-01

    Currently, the quantitative analysis of moderators affecting the function of the hypothalamus-pituitary-adrenal (HPA)-axis in health and sickness is still unreliable. This is, in particular, due to physiological factors such as pulsatile ultradian and circadian glucocorticoid secretion as well as to methodological limitations of the current techniques for steroid hormone determination. Based on this background, the determination of long-term hair steroid concentrations is an important methodological improvement allowing for the quantitative analysis of chronic HPA axis-activation. In order to determine the relationship between chronic mental and physical stress and a chronic activation of the HPA axis, we performed a cross-sectional pilot-study with 40 healthy students and examined the relationships between physical activity, mental burden(s), subjective stress perceptions, depressiveness, anxiety, physical complaints, sense of coherence, resilience, and the long-term integrated steroid hormone levels in hair. The results showed that the concentrations of cortisol, cortisone, and dehydroepiandrosterone in hair were significantly correlated to mental (p = 0.034) and physical stress (p = 0.001) as well as to subjective stress perception (p = 0.006). We conclude that steroid concentrations in hair are decisive predictors for an increase in the long-term-HPA axis activity. Moreover, this biomarker is suitable for capturing the stresslevel after burdening events and physical activity. PMID:27174654

  18. Pilot study of adrenal steroid hormones in hair as an indicator of chronic mental and physical stress

    PubMed Central

    Ullmann, E.; Barthel, A; Petrowski, K.; Stalder, T.; Kirschbaum, C.; Bornstein, S. R.

    2016-01-01

    Currently, the quantitative analysis of moderators affecting the function of the hypothalamus-pituitary-adrenal (HPA)-axis in health and sickness is still unreliable. This is, in particular, due to physiological factors such as pulsatile ultradian and circadian glucocorticoid secretion as well as to methodological limitations of the current techniques for steroid hormone determination. Based on this background, the determination of long-term hair steroid concentrations is an important methodological improvement allowing for the quantitative analysis of chronic HPA axis-activation. In order to determine the relationship between chronic mental and physical stress and a chronic activation of the HPA axis, we performed a cross-sectional pilot-study with 40 healthy students and examined the relationships between physical activity, mental burden(s), subjective stress perceptions, depressiveness, anxiety, physical complaints, sense of coherence, resilience, and the long-term integrated steroid hormone levels in hair. The results showed that the concentrations of cortisol, cortisone, and dehydroepiandrosterone in hair were significantly correlated to mental (p = 0.034) and physical stress (p = 0.001) as well as to subjective stress perception (p = 0.006). We conclude that steroid concentrations in hair are decisive predictors for an increase in the long-term-HPA axis activity. Moreover, this biomarker is suitable for capturing the stresslevel after burdening events and physical activity. PMID:27174654

  19. Dynamic pituitary-adrenal interactions in response to Cardiac surgery

    PubMed Central

    Walker, Jamie J; Russell, Georgina M; Stevenson, Kirsty; Kershaw, Yvonne; Zhao, Zidong; Henley, David; Angelini, Gianni D; Lightman, Stafford L

    2014-01-01

    corticosterone measurement. Rats were sacrificed 6 hours after the injection and the adrenal glands were collected for measurement of StAR, SF-1 and DAX1 mRNA and protein using RTqPCR and Western immunoblotting, respectively. Adrenal levels of the ACTH receptor (MC2R) mRNA and its accessory protein (MRAP) were also measured by RTqPCR. In response to LPS, rats showed a pattern of ACTH and corticosterone that was similar to patients undergoing CABG. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in StAR, SF-1 and MRAP mRNAs and StAR protein, and a reduction in DAX1 and MC2R mRNAs, 6h after LPS injection. Conclusions Severe inflammatory stimuli activate the HPA axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following CABG there is a massive increase in both ACTH and cortisol secretion. Despite a subsequent fall of ACTH to basal levels, cortisol remains elevated and co-ordinated ACTH - cortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to ACTH, which we confirmed in our animal model of immune activation of the HPA axis. Using this model we were able to show that this increased adrenal sensitivity results from changes in the regulation of both stimulatory and inhibitory intra-adrenal signaling pathways. Increased understanding of the dynamics of normal HPA responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients. PMID:25517478

  20. Gonadal steroid modulation of the limbic-hypothalamic- pituitary-adrenal (LHPA) axis is influenced by social status in female rhesus monkeys.

    PubMed

    Wilson, Mark E; Legendre, Ariadne; Pazol, Karen; Fisher, Jeffrey; Chikazawa, Kathy

    2005-03-01

    Chronic stress can have a deleterious effect on the re-productive axis that, for females, is manifested in an increased incidence of infertility. However, gonadal steroids may, in turn, affect a female's response to stress as measured by activity within the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. What is not clear is whether a history of exposure to stress modifies the effect of gonadal steroids on LHPA responsivity. Rhesus monkeys present a unique opportunity to assess LHPA responsivity when housed socially in groups. Under these situations, monkeys exhibit a rich network of affiliation and have established social status hierarchies. Previous work indicates that socially subordinate macaque females are hypercortisolemic due to diminished gluco-corticoid negative feedback. The present study tested the hypothesis that estradiol (E2) would decrease gluco-corticoid negative feedback, assessed from a dexamethasone (DEX) suppression test, and increase the response to corticotropin releasing factor (CRF) and that these effects would be attenuated by co-treatment with P4. In addition, we also determined whether E2 and P4 would differentially affect LHPA responsiveness to pharmacological challenge in socially dominant compared with subordinate females. Endogenous gonadal hormone secretion in female rhesus monkeys (n = 7) was suppressed by continuous treatment with a sustained release formulation of the GnRH analog leuprolide acetate (Lupron Depot). The response to a combined DEX suppression-CRF stimulation test was assessed using a counterbalanced design during a placebo (control) treatment condition and during E2, P4, and E2 + P4 re-placement therapy. Females who were members of a large breeding group of 140 adults and juveniles of both sexes, were classified as dominant (n = 4) or subordinate (n = 3) based on the relative social dominance positions within the group. Plasma levels of cortisol were significantly higher during E2 replacement compared to the other

  1. Environmental enrichment mitigates the sex-specific effects of gestational inflammation on social engagement and the hypothalamic pituitary adrenal axis-feedback system.

    PubMed

    Connors, E J; Shaik, A N; Migliore, M M; Kentner, A C

    2014-11-01

    Modest environmental enrichment (EE) is well recognized to protect and rescue the brain from the consequences of a variety of insults. Although animal models of maternal immune activation (MIA) are associated with several neurodevelopmental impairments in both the behavioral and cognitive functioning of offspring, the impact of EE in protecting or reversing these effects has not been fully evaluated. In the present study, female Sprague-Dawley rats were randomized into EE (pair-housed in a large multi-level cage with toys, tubes and ramps) or animal care control (ACC; pair-housed in standard cages) conditions. Each pair was bred, following assignment to their housing condition, and administered 100μg/kg of lipopolysaccharide (LPS) on gestational day 11. After birth, and until the end of the study, offspring were maintained in their respective housing conditions. EE protected against both the social and hypothalamic pituitary adrenal axis consequences of MIA in juvenile male rats, but surprisingly not against the spatial discrimination deficits or accompanying decrease in glutamate levels within the hippocampus (as measured via LCMS-MS). Based on these preliminary results, the mechanisms that underlie the sex-specific consequences that follow MIA appear to be dependent on environmental context. Together, this work highlights the importance of environmental complexity in the prevention of neurodevelopmental deficits following MIA.

  2. Influence of the hypothalamic-pituitary-adrenal axis on the menstrual cycle and the pituitary responsiveness to estradiol in the female rhesus monkey (Macaca mulatta).

    PubMed

    Hayashi, K T; Moberg, G P

    1990-02-01

    In order to examine the effect of glucocorticoids on the menstrual cycle of rhesus monkeys, cortisol was injected twice daily during the follicular phase. This cortisol treatment did not alter basal gonadotropin secretion but blocked the normal follicular rise of estrogens, the gonadotropin surge and the luteal rise of progesterone, and delayed the onset of the next cycle. In a second study, estradiol benzoate (E2B) was injected on the sixth day following the start of menstrual bleeding either with or without concurrent adrenocorticotropic hormone (ACTH) treatment. E2B injection was able to stimulate surges of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) whether or not the animals had been treated with ACTH. These data suggest that, the action of cortisol, the final mediating step in the hypothalamic-pituitary-adrenal axis, occurs at the level of the gonads versus the pituitary in the rhesus monkey. While the pituitary response to endogenous gonadotropin-releasing hormone or exogenous E2B stimulation appears to remain unaffected, normal folliculogenesis is disrupted, preventing the follicular secretion of estrogens and the subsequent gonadotropin surges. The effects of corticosteroids are temporary, with normal cycling returning when plasma corticosteroids return to basal concentrations, albeit after a delay.

  3. A Fall in Plasma Free Fatty Acid (FFA) Level Activates the Hypothalamic-Pituitary-Adrenal Axis Independent of Plasma Glucose: Evidence for Brain Sensing of Circulating FFA

    PubMed Central

    Oh, Young Taek; Oh, Ki-Sook; Kang, Insug

    2012-01-01

    The brain responds to a fall in blood glucose by activating neuroendocrine mechanisms for its restoration. It is unclear whether the brain also responds to a fall in plasma free fatty acids (FFA) to activate mechanisms for its restoration. We examined whether lowering plasma FFA increases plasma corticosterone or catecholamine levels and, if so, whether the brain is involved in these responses. Plasma FFA levels were lowered in rats with three independent antilipolytic agents: nicotinic acid (NA), insulin, and the A1 adenosine receptor agonist SDZ WAG 994 with plasma glucose clamped at basal levels. Lowering plasma FFA with these agents all increased plasma corticosterone, but not catecholamine, within 1 h, accompanied by increases in plasma ACTH. These increases in ACTH or corticosterone were abolished when falls in plasma FFA were prevented by Intralipid during NA or insulin infusion. In addition, the NA-induced increases in plasma ACTH were completely prevented by administration of SSR149415, an arginine vasopressin receptor antagonist, demonstrating that the hypothalamus is involved in these responses. Taken together, the present data suggest that the brain may sense a fall in plasma FFA levels and activate the hypothalamic-pituitary-adrenal axis to increase plasma ACTH and corticosterone, which would help restore FFA levels. Thus, the brain may be involved in the sensing and control of circulating FFA levels. PMID:22669895

  4. Stress during pregnancy alters the offspring hypothalamic, pituitary, adrenal, and testicular response to isolation on the day of weaning.

    PubMed

    Williams, M T; Davis, H N; McCrea, A E; Hennessy, M B

    1999-01-01

    Subjecting pregnant female rats to situations that activate the hypothalamic-pituitary-adrenal (HPA) axis can have long-term effects on the development of the offspring. Restraint under bright lights is a common method of stressing pregnant females that results in consistent behavioral changes in the offspring. We investigated the effects of gestationally administered restraint, bright lights, and heat on the HPA axis response of 21-day-old offspring following exposure to isolation in a novel environment or under resting conditions. Corticotropin-releasing factor titers in the hypothalamus were unaffected following isolation. Nonetheless, adrenocorticotropin hormone (ACTH) was found to be lower in the gestationally stressed offspring prior to or following the isolation period. Corticosterone was attenuated in gestationally stressed offspring following the postnatal stressor and there was also a tendency for the gestationally stressed females to have lower concentrations of aldosterone. Plasmatic testosterone levels were higher in the gestationally stressed males following the period of isolation. The present data suggest that the HPA axis of the offspring is differentially affected by the gestational stress procedure, that is, it is attenuated at the level of the pituitary and adrenal, but not at the level of the hypothalamus. These data have implications for behavioral differences observed in gestationally stressed animals.

  5. Adrenal glands

    MedlinePlus

    ... disorders , infections, tumors, and bleeding. Related topics: Addison disease Adrenal insufficiency Congenital adrenal hyperplasia Cushing syndrome Diabetes mellitus - secondary Glucocorticoid medications Hirsutism Hump ...

  6. Gender difference in alcohol-evoked hypothalamic-pituitary-adrenal activity in the rat: ontogeny and role of neonatal steroids.

    PubMed

    Ogilvie, K M; Rivier, C

    1996-04-01

    Alcohol administration results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, with female rats secreting more adrenocorticotropin (ACTH) and corticosterone (B) than males in response to the same dose of alcohol. We first examined the ontogeny of the gender difference in HPA responsiveness to alcohol by administering four doses (0, 1, 2, or 3 g/kg body weight) to animals at 21, 41, and 61 days of age (prepubertal, peripubertal, and postpubertal, respectively). We then investigated the organizational role of steroids by manipulating the neonatal steroidal milieu. Rats of both genders were gonadectomized or injected with testosterone propionate within 24 hr of birth and the HPA response to 3 g/kg body weight alcohol was tested in adulthood (postpubertal period). Our data show that the gender difference in HPA responsiveness to alcohol administration arises peripubertally. In addition, HPA response to alcohol is quantitatively smaller in intact male rats than in feminized groups (gonadectomized males and females, intact females) and masculinized female rats. We conclude that the gender difference in HPA response to alcohol observed in postpubertal rats injected with alcohol depends on the activational role of testicular androgens, rather than on their organizational influence.

  7. Gonadectomy reverses the sexually diergic patterns of circadian and stress-induced hypothalamic-pituitary-adrenal axis activity in male and female rats.

    PubMed

    Seale, J V; Wood, S A; Atkinson, H C; Bate, E; Lightman, S L; Ingram, C D; Jessop, D S; Harbuz, M S

    2004-06-01

    Enhanced corticosterone release by female compared to male rats under basal and stress conditions is well documented. The demonstration that gonadectomy enhances stress-induced corticosterone secretion in male rats, but reduces such levels in female rats, suggests a causal association between gonadal steroids and corticosterone release. The present study examined the corticosterone profile of sham gonadectomized and gonadectomized female and male rats under basal and stress conditions. An automated sampling system collected blood from each freely moving, unanaesthetized rat every 10 min (i) over a 24-h period; (ii) following noise stress; and (iii) following an immune-mediated stress (lipopolysaccharide, LPS). Plasma was analysed for corticosterone content using radioimmunoassay. Castration resulted in a significant increase in basal corticosterone release compared to the sham-castrated male rats. Pulsar analysis revealed a significant two-fold increase in the number of corticosterone pulses over 24 h. Corticosterone increases in response to noise stress and to LPS injection were enhanced following castration. Conversely, ovariectomy resulted in a two-fold reduction in the number of corticosterone pulses as well as the stress response compared to sham-ovariectomized female rats. Arginine vasopressin (AVP), corticotrophin-releasing hormone (CRH) and glucocorticoid receptor mRNAs in the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary were analysed post-LPS administration by in situ hybridization. Significantly higher values were found for AVP, CRH and POMC mRNAs examined for sham females and castrated males compared to sham males and ovariectomized females. This study confirms previous reports concerning the influence of gonadal factors in regulating HPA axis activity and stress responsiveness. The present results extend these observations to the regulation of the dynamic pattern of corticosterone release under basal conditions

  8. Acute hypernatremia promotes anxiolysis and attenuates stress-induced activation of the hypothalamic-pituitary-adrenal axis in male mice

    PubMed Central

    Smith, Justin A.; Wang, Lei; Hiller, Helmut; Taylor, Christopher T.; de Kloet, Annette D.; Krause, Eric G.

    2014-01-01

    Previous investigation by our laboratory found that acute hypernatremia potentiates an oxytocinergic tone that inhibits parvocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus (PVN), attenuates restraint-induced surges in corticosterone (CORT), and reduces anxiety-like behavior in male rats. To investigate the neural mechanisms mediating these effects and extend our findings to a more versatile species, we repeated our studies using laboratory mice. In response to 2.0 M NaCl injections, mice had increased plasma sodium concentrations which were associated with a blunted rise in CORT subsequent to restraint challenge relative to 0.15 M NaCl injected controls. Immunofluorescent identification of the immediate early gene product Fos found that 2.0 M NaCl treatment increased the number of activated neurons producing oxytocin in the PVN. To evaluate the effect of acute hypernatremia on PVN neurons producing corticotropin-releasing hormone (CRH), we used the Cre-lox system to generate mice that produced the red fluorescent protein, tdTomato, in cells that had Cre-recombinase activity driven by CRH gene expression. Analysis of brain tissue from these CRH-reporter mice revealed 2.0 M NaCl treatment caused a dramatic reduction in Fos-positive nuclei specifically in CRH-producing PVN neurons. This altered pattern of activity was predictive of alleviated anxiety-like behavior as mice administered 2.0 M NaCl spent more time exploring the open arms of an elevated-plus maze than 0.15 M NaCl treated controls. Taken together, these results further implicate an oxytocin-dependent inhibition of CRH neurons in the PVN and demonstrate the impact that slight elevations in plasma sodium have on hypothalamic-pituitary-adrenocortical axis output and anxiety-like behavior. PMID:24704193

  9. [Effects of quinazoline-2, 4(1H, 3H)-dione compound, H-88 and pyridopyrimidine-2, 4(1H, 3H)-dione compound, HN-37 on pituitary-adrenal axis in rats (author's transl)].

    PubMed

    Tsuji, M; Saita, M; Soejima, Y; Takamori, M; Noda, K; Ueki, S; Fujiwara, M

    1980-11-01

    Anti-carrageenin paw edema effects of 1-(m-trifluoromethylphenyl)-3-(2-hydroxyethyl)-quinazoline-2, 4(1H, 3H)-dione [H-88] and 1-(m-trifluoromethylphenyl)-3-ethylpyridopyrimidine-2, 4(1H, 3H)-dione [HN-37] in rats were dissipated or reduced markedly by adrenalectomy. The effects of both compounds on the pituitary-adrenal axis were therefore investigated in male Wistar rats at 5-6 weeks of age. Oral treatments with H-88 in a dose of 100 mg/kg and HN-37 at 10 mg/kg induced the same degree of responses in intact animals, namely, a marked increase of blood corticosterone level at one hr of the peak time (360%), a decrease of adrenal ascorbic acid level at 3 hr (52-59%), an increase of blood glucose level at 6-12 hr (25-59%) and of liver glycogen level at 12-4 hr (97-153%). In addition, a significant hypertrophy of the pituitary and adrenals (p less than 0.05) at 6-12 hr and/or atrophy of the thymus and spleen at 3-24 hr were noted. The effect of HN-37 on blood corticosterone level was approximately 10 times as potent as that of H-88 as well as on the carrageenin paw edema. The effects of both compounds on blood corticosterone level were dissipated by adrenalectomy, and those on blood corticosterone level and adrenal ascorbic acid level were abolished by hypophysectomy. These results suggest that hypophysis-adrenal axis stimulation may play an important role in antiedematous effects of N-88 and HN-37.

  10. Adrenocorticotropin (ACTH) and corticosterone secretion by perifused pituitary and adrenal glands from rodents exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD).

    PubMed

    Pitt, J A; Buckalew, A R; House, D E; Abbott, B D

    2000-10-26

    Although in utero maternal stress has been shown to have lasting effects on rodent offspring, fetal effects of chemically-induced alterations of the maternal hypothalamic-pituitary-adrenal axis (HPA) have not been well studied. This study examined the effects of in vivo 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on pituitary-adrenal function in the male rat, pregnant female rat and pregnant female mouse. The secretion of adrenocorticotropin (ACTH) and corticosterone (CORT) in pituitary and adrenal glands, respectively, was assessed in ex vivo perifusion cultures. Male and pregnant female (gestation day 8) Sprague-Dawley rats were gavaged once with 10 microgram/kg TCDD, pregnant female mice once with 24 microgram/kg TCDD, and euthanized 10 days later. Hemi-pituitary (rat) or whole anterior pituitaries (mice) and right adrenal glands from the same animal were quartered, perifused under baseline and stimulated conditions. In both males and pregnant females, TCDD did not affect corticotropin releasing hormone (CRH)-stimulated ACTH secretion. Neither total pituitary ACTH nor plasma ACTH was altered in either sex or species by TCDD treatment. ACTH-stimulated CORT secretion was not affected by TCDD in either sex or species, and adrenal tissue and plasma CORT levels were unchanged in males and pregnant females by TCDD. However, the plasma ACTH:CORT ratio was decreased about 46% in male rats treated with TCDD. Plasma CORT levels were 23-fold higher and plasma ACTH levels were 1.5-fold higher in pregnant females than in male rats. In male versus female rats, adrenal CORT and anterior pituitary ACTH tissue levels were about 7.5- and 1.75-fold higher and ACTH, respectively. Female mouse adrenal tissue CORT was about 4-fold greater than female rat. The reduced plasma ACTH:CORT ratio in the male rat suggests that TCDD disturbs HPA function. Exposure of male rat to a 5-fold higher dose in earlier studies clearly demonstrated effects of TCDD on male rat HPA. The present

  11. Developmental and contextual considerations for adrenal and gonadal hormone functioning during adolescence: Implications for adolescent mental health.

    PubMed

    Marceau, Kristine; Ruttle, Paula L; Shirtcliff, Elizabeth A; Essex, Marilyn J; Susman, Elizabeth J

    2015-09-01

    Substantial research has implicated the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes independently in adolescent mental health problems, though this literature remains largely inconclusive. Given the cross-talk between the HPA and HPG axes and their increased activation in adolescence, a dual-axis approach that examines both axes simultaneously is proposed to predict the emergence and persistence of adolescent mental health problems. After briefly orienting readers to HPA and HPG axis functioning, we review the literature examining associations between hormone levels and changes with behavior during adolescence. Then, we provide a review of the literature supporting examination of both axes simultaneously and present the limited research that has taken a dual-axis approach. We propose future directions including consideration of between-person and within-person approaches to address questions of correlated changes in HPA and HPG hormones. Potential moderators are considered to increase understanding of the nuanced hormone-behavior associations during key developmental transitions.

  12. Developmental and Contextual Considerations for Adrenal and Gonadal Hormone Functioning During Adolescence: Implications for Adolescent Mental Health

    PubMed Central

    Ruttle, Paula L.; Shirtcliff, Elizabeth A.; Essex, Marilyn J.; Susman, Elizabeth J.

    2014-01-01

    Substantial research has implicated the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes independently in adolescent mental health problems, though this literature remains largely inconclusive. Given the cross-talk between the HPA and HPG axes and their increased activation in adolescence, a dual-axis approach that examines both axes simultaneously is proposed to predict the emergence and persistence of adolescent mental health problems. After briefly orienting readers to HPA and HPG axis functioning, we review the literature examining associations between hormone levels and changes with behavior during adolescence. Then, we provide a review of the literature supporting examination of both axes simultaneously and present the limited research that has taken a dual-axis approach. We propose future directions including consideration of between-person and within-person approaches to address questions of correlated changes in HPA and HPG hormones. Potential moderators are considered to increase understanding of the nuanced hormone–behavior associations during key developmental transitions. PMID:24729154

  13. Androgens alter corticotropin releasing hormone and arginine vasopressin mRNA within forebrain sites known to regulate activity in the hypothalamic-pituitary-adrenal axis.

    PubMed

    Viau, V; Soriano, L; Dallman, M F

    2001-05-01

    To reveal direct effects of androgens, independent of glucocorticoids, we studied the effects of gonadectomy (GDX) in adrenalectomized (ADX) rats with or without androgen replacement on corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) mRNA expression within various forebrain sites known to regulate the hypothalamic-pituitary-adrenal axis. These included the medial parvocellular portion of the paraventricular nucleus of the hypothalamus (mp PVN), the central and medial nuclei of the amygdala and bed nuclei of the stria terminalis (BNST). In the mp PVN, ADX stimulated both CRH and AVP mRNA expression. Combined ADX + GDX inhibited only AVP, and testosterone and dihydrotestosterone (DHT) restored AVP mRNA. In the central nucleus of the amygdala, ADX decreased CRH mRNA expression, and this response was unaffected by GDX +/- testosterone or DHT replacement. In the medial amygdala, AVP mRNA expression was decreased by ADX, abolished by ADX + GDX, and restored by androgen replacement. ADX had no effect on CRH and AVP mRNA expression in the BNST. GDX + ADX, however, reduced CRH mRNA expression only within the fusiform nuclei of the BNST and reduced the number of AVP-expressing neurones in the posterior BNST. Androgen replacement reversed both responses. In summary, in ADX rats, AVP, but not CRH mRNA expression in the amygdala and mp PVN, is sensitive to GDX +/- androgen replacement. Both CRH- and AVP-expressing neurones in the BNST respond to GDX and androgen replacement, but not to ADX alone. Because androgen receptors are not expressed by hypophysiotropic PVN neurones, we conclude that glucocorticoid-independent, androgenic influences on medial parvocellular AVP mRNA expression are mediated upstream from the PVN, and may involve AVP-related pathways in the medial amygdala, relayed to and through CRH- and AVP-expressing neurones of the BNST.

  14. Effects of early- and late-gestational maternal stress and synthetic glucocorticoid on development of the fetal hypothalamus-pituitary-adrenal axis in sheep.

    PubMed

    Rakers, Florian; Frauendorf, Vilmar; Rupprecht, Sven; Schiffner, Rene; Bischoff, Sabine J; Kiehntopf, Michael; Reinhold, Petra; Witte, Otto W; Schubert, Harald; Schwab, Matthias

    2013-01-01

    Prenatal maternal stress (PMS) programs dysregulation of the hypothalamus-pituitary-adrenal axis (HPAA) in postnatal life, though time periods vulnerable to PMS, are still unclear. We evaluated in pregnant sheep the effect of PMS during early gestation [30-100 days of gestation (dGA); term is 150 dGA] or late gestation (100-120 dGA) on development of fetal HPAA function. We compared the effects of endogenous cortisol with synthetic glucocorticoid (GC) exposure, as used clinically to enhance fetal lung maturation. Pregnant sheep were exposed to repeated isolation stress twice per week for 3 h in a separate box with no visual, tactile, or auditory contact with their flock-mates either during early (n = 7) or late (n = 7) gestation. Additional groups received two courses of betamethasone (BM; n = 7; 2 × 110 μg kg(- 1) body weight, 24 h apart) during late gestation (106/107 and 112/113 dGA, n = 7) or acted as controls (n = 7). Fetal cortisol responses to hypotensive challenge, a physiological fetal stressor, were measured at 112 and 129 dGA, i.e. before and during maturation of the HPAA. Hypotension was induced by fetal infusion of sodium nitroprusside, a potent vasodilator. At 112 dGA, neither PMS nor BM altered fetal cortisol responses. PMS, during early or late gestation, and BM treatment increased fetal cortisol responses at 129 dGA with the greatest increase achieved in stressed early pregnant sheep. Thus, development of the HPAA is vulnerable to inappropriate levels of GCs during long periods of fetal life, whereas early gestation is most vulnerable to PMS.

  15. Adaptation of the pituitary-adrenal axis to daily repeated forced swim exposure in rats is dependent on the temperature of water.

    PubMed

    Rabasa, Cristina; Delgado-Morales, Raúl; Gómez-Román, Almudena; Nadal, Roser; Armario, Antonio

    2013-11-01

    Comparison of exposure to certain predominantly emotional stressors reveals a qualitatively similar neuroendocrine response profile as well as a reduction of physiological responses after daily repeated exposure (adaptation). However, particular physical components of the stressor may interfere with adaptation. As defective adaptation to stress can enhance the probability to develop pathologies, we studied in adult male rats (n = 10/group) swimming behavior (struggling, immobility and mild swim) and physiological responses (ACTH, corticosterone and rectal temperature) to daily repeated exposure to forced swim (20 min, 13 d) at 25 or 36 °C (swim25 or swim36). Rats were repeatedly blood-sampled by tail-nick and hormones measured by radioimmunoassay. Some differences were observed between the two swim temperature groups after the first exposure to forced swim: (a) active behaviors were greater in swim25 than swim36 groups; (b) swim25 but not swim36 caused hypothermia; and (c) swim36 elicited the same ACTH response as swim25, but plasma corticosterone concentration was lower for swim36 at 30 min post-swim. After daily repeated exposure, adaptation in ACTH secretion was observed with swim36 already on day 4, whereas with swim25 adaptation was not observed until day 13 and was of lower magnitude. Nevertheless, after repeated exposure to swim25 a partial protection from hypothermia was observed and the two swim conditions resulted in progressive reduction of active behaviors. Thus, daily repeated swim at 25 °C impairs adaptation of the hypothalamic-pituitary-adrenal axis as compared to swim at 36 °C, supporting the hypothesis that certain physical components of predominantly emotional stressors can interfere with the process of adaptation.

  16. Antidepressant-Like Effects of Fractions Prepared from Danzhi-Xiaoyao-San Decoction in Rats with Chronic Unpredictable Mild Stress: Effects on Hypothalamic-Pituitary-Adrenal Axis, Arginine Vasopressin, and Neurotransmitters

    PubMed Central

    Wu, Li-Li; Liu, Yan; Pan, Yi; Su, Jun-Fang; Wu, Wei-Kang

    2016-01-01

    The aim of the present study was to investigate the antidepressant-like effects of two fractions, including petroleum ether soluble fraction (Fraction A, FA) and water-EtOH soluble fraction (Fraction B, FB) prepared from the Danzhi-xiaoyao-san (DZXYS) by using chronic unpredictable mild stress-induced depressive rat model. The results indicated that DZXYS could ameliorate the depression-like behavior in chronic stress model of rats. The inhibition of hyperactivity of HPA axis and the modulation of monoamine and amino acid neurotransmitters in the hippocampus may be the important mechanisms underlying the action of DZXYS antidepressant-like effect in chronically stressed rats. PMID:27413389

  17. Antidepressant-Like Effects of Fractions Prepared from Danzhi-Xiaoyao-San Decoction in Rats with Chronic Unpredictable Mild Stress: Effects on Hypothalamic-Pituitary-Adrenal Axis, Arginine Vasopressin, and Neurotransmitters.

    PubMed

    Wu, Li-Li; Liu, Yan; Yan, Can; Pan, Yi; Su, Jun-Fang; Wu, Wei-Kang

    2016-01-01

    The aim of the present study was to investigate the antidepressant-like effects of two fractions, including petroleum ether soluble fraction (Fraction A, FA) and water-EtOH soluble fraction (Fraction B, FB) prepared from the Danzhi-xiaoyao-san (DZXYS) by using chronic unpredictable mild stress-induced depressive rat model. The results indicated that DZXYS could ameliorate the depression-like behavior in chronic stress model of rats. The inhibition of hyperactivity of HPA axis and the modulation of monoamine and amino acid neurotransmitters in the hippocampus may be the important mechanisms underlying the action of DZXYS antidepressant-like effect in chronically stressed rats. PMID:27413389

  18. Reversal of the hypothalamo-pituitary-adrenal response to oestrogens around puberty.

    PubMed

    Evuarherhe, Obaro; Leggett, James; Waite, Eleanor; Kershaw, Yvonne; Lightman, Stafford

    2009-08-01

    The neuroendocrine gender dimorphism that begins during perinatal development is completed during puberty. We have previously described how the perinatal gonadal steroids programme hypothalamic-pituitary-adrenal (HPA) activity in adulthood and we now assess the role of peripubertal ovarian hormones. Prepubertal females were treated subcutaneously with either cholesterol or 17beta-oestradiol and their pituitary-adrenal activity was assessed 5 days later. Oestradiol suppressed the ACTH and corticosterone responses to restraint stress in the prepubertal female. Furthermore, groups of female rats were ovariectomised (OVX) either before or after puberty and adult animals were subsequently treated with subcutaneous implants containing either 17beta-oestradiol or cholesterol. Corticosterone pulsatility was assessed using an automated blood sampling system to collect blood from freely moving animals at 10 min intervals over 24 h. Oestradiol administered to adults that had been OVX either pre- or post-pubertally displayed a significantly higher mean corticosterone level as well as increased pulse frequency and pulse amplitude compared with cholesterol treated controls. These data demonstrate a reversal in the effect of oestrogens on HPA axis activity over the time of puberty with inhibitory effects prepubertally and stimulatory actions after puberty and imply an ovarian steroid-independent mechanism of pubertal maturation of HPA sensitivity to oestrogens.

  19. Crossover of the hypothalamic pituitary-adrenal/interrenal, -thyroid, and -gonadal axes in testicular development.

    PubMed

    Castañeda Cortés, Diana C; Langlois, Valerie S; Fernandino, Juan I

    2014-01-01

    Besides the well-known function of thyroid hormones (THs) for regulating metabolism, it has recently been discovered that THs are also involved in testicular development in mammalian and non-mammalian species. THs, in combination with follicle stimulating hormone, lead to androgen synthesis in Danio rerio, which results in the onset of spermatogenesis in the testis, potentially relating the hypothalamic-pituitary-thyroid (HPT) gland to the hypothalamic-pituitary-gonadal (HPG) axes. Furthermore, studies in non-mammalian species have suggested that by stimulating the thyroid-stimulating hormone (TSH), THs can be induced by corticotropin-releasing hormone. This suggests that the hypothalamic-pituitary-adrenal/interrenal gland (HPA) axis might influence the HPT axis. Additionally, it was shown that hormones pertaining to both HPT and HPA could also influence the HPG endocrine axis. For example, high levels of androgens were observed in the testis in Odonthestes bonariensis during a period of stress-induced sex-determination, which suggests that stress hormones influence the gonadal fate toward masculinization. Thus, this review highlights the hormonal interactions observed between the HPT, HPA, and HPG axes using a comparative approach in order to better understand how these endocrine systems could interact with each other to influence the development of testes.

  20. Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens

    PubMed Central

    Fallahsharoudi, Amir; de Kock, Neil; Johnsson, Martin; Ubhayasekera, S. J. Kumari A.; Bergquist, Jonas; Wright, Dominic; Jensen, Per

    2015-01-01

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal. PMID:26471470

  1. Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens.

    PubMed

    Fallahsharoudi, Amir; de Kock, Neil; Johnsson, Martin; Ubhayasekera, S J Kumari A; Bergquist, Jonas; Wright, Dominic; Jensen, Per

    2015-01-01

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal. PMID:26471470

  2. Domestication Effects on Stress Induced Steroid Secretion and Adrenal Gene Expression in Chickens.

    PubMed

    Fallahsharoudi, Amir; de Kock, Neil; Johnsson, Martin; Ubhayasekera, S J Kumari A; Bergquist, Jonas; Wright, Dominic; Jensen, Per

    2015-10-16

    Understanding the genetic basis of phenotypic diversity is a challenge in contemporary biology. Domestication provides a model for unravelling aspects of the genetic basis of stress sensitivity. The ancestral Red Junglefowl (RJF) exhibits greater fear-related behaviour and a more pronounced HPA-axis reactivity than its domesticated counterpart, the White Leghorn (WL). By comparing hormones (plasmatic) and adrenal global gene transcription profiles between WL and RJF in response to an acute stress event, we investigated the molecular basis for the altered physiological stress responsiveness in domesticated chickens. Basal levels of pregnenolone and dehydroepiandrosterone as well as corticosterone response were lower in WL. Microarray analysis of gene expression in adrenal glands showed a significant breed effect in a large number of transcripts with over-representation of genes in the channel activity pathway. The expression of the best-known steroidogenesis genes were similar across the breeds used. Transcription levels of acute stress response genes such as StAR, CH25 and POMC were upregulated in response to acute stress. Dampened HPA reactivity in domesticated chickens was associated with changes in the expression of several genes that presents potentially minor regulatory effects rather than by means of change in expression of critical steroidogenic genes in the adrenal.

  3. Body-fat distribution and responsiveness of the pituitary-adrenal axis to corticotropin-releasing-hormone stimulation in sedentary and exercising women.

    PubMed

    Fabbri, A; Giannini, D; Aversa, A; De Martino, M U; Fabbrini, E; Franceschi, F; Moretti, C; Frajese, G; Isidori, A

    1999-05-01

    Excess upper-body (android) fat is considered an health hazard. Exercise training is known to have the potential to modify body composition and to induce a preferential loss of abdominal fat. We studied and compared the composition of whole body and major body regions using dual-energy X-ray absorptiometry (DEXA) in 21 exercising (3-4 hours of intense physical activity/day) and 21 sedentary eumenorrhoic women of similar ages, body mass index (BMI), waist-to-hip ratio (WHR) and age of menarche. In a small number of women in each group (6 out of 21), the ACTH and cortisol response to CRH test and the 24-h urinary cortisol excretion was evaluated. Exercising women had 10% higher total and leg lean mass (p<0.05), and 38% lower total fat mass (p<0.01) than sedentary women. Furthermore, the proportion of android fat was 22% lower in exercising than sedentary women (p<0.01), while the proportion of lower-body (gynoid fat) was unchanged. BMI and WHR were not different between the two groups, while the android/gynoid fat ratios were 16% lower in exercising than in sedentary women (p<0.01). In the exercising women, ACTH and cortisol plasma levels, as well as the 24-h urinary cortisol excretion, were significantly (p<0.01) higher than in the sedentary women studied. In these subjects, a direct relationship between the peak delta percentage increases of ACTH and cortisol after the CRH test and the proportion of android fat was found (r=0.60, p<0.05 and r=0.69, p<0.02, respectively). These results demonstrate that in women who practise intense exercise there are significant differences in body fat distribution in comparison to sedentary women, with a marked less amount of android fat, and suggest that this difference may be related to a reduced response of the pituitary-adrenal axis to CRH. PMID:10401712

  4. Lack of hypothalamic-pituitary-adrenal axis suppression with once-daily or twice-daily beclomethasone dipropionate aqueous nasal spray administered to patients with allergic rhinitis.

    PubMed

    Brannan, M D; Herron, J M; Reidenberg, P; Affrime, M B

    1995-01-01

    The potential for a newly developed, double-strength (0.084%) beclomethasone dipropionate (BDP) aqueous (AQ) nasal suspension to produce effects associated with exposure to systemic corticosteroids was assessed by the plasma cortisol response to cosyntropin stimulation induced by a 6-hour intravenous infusion of 250 micrograms of cosyntropin in 500 mL of normal saline. Sixty-four patients with allergic rhinitis were enrolled in this study. Patients were randomly assigned to one of the following four treatment groups: (1) BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily; (2) BDP AQ (0.042%) nasal spray 168 micrograms twice daily; (3) placebo nasal spray twice daily; or (4) oral prednisone 10 mg once daily in the morning. After 36 consecutive days of treatment, there was a significant (P < 0.01) difference in the plasma cortisol response to cosyntropin stimulation between the prednisone and placebo groups; however, there were no significant differences between the BDP AQ Forte or the BDP AQ groups compared with the placebo group. Secondary analyses comparing BDP AQ Forte administered as 336 micrograms once daily with BDP AQ administered as 168 micrograms twice daily showed no significant differences in plasma cortisol responses to cosyntropin stimulation. No serious adverse events were reported. Adverse events consisted of headache, pharyngitis, or nasal irritation, with headache being reported most frequently. These adverse events were similarly distributed among active treatment groups and were similar to placebo. No clinically relevant changes were observed in any treatment group in findings on clinical laboratory tests, physical examination, or electrocardiography. Vital signs, obtained daily, were consistent with values observed in healthy individuals. No patient exhibited signs of oral candidiasis. All patients met the plasma cortisol concentration criteria for discharge relative to expected hypothalamic-pituitary-adrenal axis function. In conclusion

  5. Adrenal sensitivity to stress is maintained despite variation in baseline glucocorticoids in moulting seals

    PubMed Central

    Champagne, Cory; Tift, Michael; Houser, Dorian; Crocker, Daniel

    2015-01-01

    Stressful disturbances activate the hypothalamic–pituitary–adrenal (HPA) axis and result in the release of glucocorticoid (GC) hormones. This characteristic stress response supports immediate energetic demands and subsequent recovery from disturbance. Increased baseline GC concentrations may indicate chronic stress and can impair HPA axis function during exposure to additional stressors. Levels of GCs, however, vary seasonally and with life-history