HPA

1. HPA Hypothalamus-Pituitary-Adrenal Axis

2. Definition •The hypothalamic-pituitary-adrenal axis or HPA, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland, and the adrenal glands. •The HPA, though traditionally seen as the body’s “stress system”, should instead be thought of as the body's energy regulator. It is ultimately responsible for controlling: virtually all of the hormones, nervous system activity and energy expenditure in the human body, as well as modulating the immune system.

3. Structure Key elements: • paraventricular nucleus of the hypothalamus • anterior lobe of the pituitary gland • adrenal cortex

7. Function •As stated earlier, the interactions among the hypothalamus, pituitary gland, and adrenal glands make up the HPA axis. •The HPA Axis is a major part of the neuroendocrine system that controls: –reactions to stress –regulates many body processes (including digestion) –the immune system –mood and emotions –sexuality and energy storage –Expenditure

8. Neuroendocrine System •So, as part of the neuroendocrine system, the HPA Axis involves interactions between the nervous and endocrine systems. These systems are known to work together to regulate the physiological processes of the human body. •This compound system, of the nervous and endocrine systems, came about from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and from there we have become aware of numerous other interconnections of the endocrine and nervous systems.

9. Function •These interactions among glands, hormones, and parts of the midbrain mediate the general adaptation syndrome (GAS): –GAS: how the body reacts to a stressor, real or imagined, a stimulus that causes stress. Acute stressors affect an organism in the short term; chronic stressors over the longer term. •Even though steroids are produced only by vertebrates (animals with a backbone), the physiological role of the HPA axis and corticosteroids in stress response is so fundamental that similar systems can be found in invertebrates and monocellular organisms as well.

10. Function: CRH •Corticotropin-releasing hormone (CRH) is a peptide hormone and neurotransmitter involved in the stress response. •Stress, physical activity, illness, blood levels of cortisol and the sleep/wake cycle influence the release of CRH from the hypothalamus. •In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30–45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night.

11. Function •Anatomical connections between brain areas such as the amygdala, hippocampus, and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the central nucleus, which projects to several parts of the brain involved in responses to fear. At the hypothalamus, fear-signaling impulses activate both the sympathetic nervous system and the modulating systems of the HPA axis. •Increased production of cortisol mediates alarm reactions to stress, facilitating an adaptive phase of a general adaptation syndrome in which alarm reactions including the immune response are suppressed, allowing the body to attempt countermeasures.

12. Function •Glucocorticoids have many important functions, including modulation of stress reactions, but in excess they can be damaging. Atrophy, the partial or complete wasting away, of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids. Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress.

13. HPA Axis and Stress • Stress can be defined biologically as what happens when an organism fails to respond appropriately to threats. • Stress involves both psychological and physiological factors. • Some stress can be beneficial; however, when it reaches chronic and harmful levels, it can cause deleterious effects such as compromised immune function, weight gain, developmental impairment, etc. • The HPA axis is responsible for coordinating the hormonal response to stress.

14. The Stress Response Stimulated by an environmental stressor, neurons in the hypothalamus secrete CRH and vassopressin. CRH is transported to the anterior pituitary, where it stimulates the secretion of corticotropin, which stimulates increased production of cortisol, the primary actor directly impacting the stress response. Vasopressin increases reabsorption of water by the kidneys and induces vasoconstriction, the contraction of blood vessels, thereby raising blood pressure. Together, CRH and vasopressin activate the hypothalamic-pituitary-adrenal (HPA) axis.

15. HPA Axis and Post Traumatic Stress Disorder (PTSD) • PTSD is a severe anxiety disorder that can develop after exposure to any event that results in physical and/or emotional trauma. • During traumatic experiences the high levels of stress hormones secreted suppress hypothalamic activity which may be a major factor towards the development of PTSD. • PTSD patients often show low cortisol levels. Cortisol’s main function is to restore homeostasis following exposure to stress. • Brain catecholamine levels and corticotropin-releasing hormone (CRH) concentrations are high. Together, these findings suggest abnormality in the hypothalamic-pituitary-adrenal (HPA) axis.

16. HPA Axis and PTSD • PTSD causes biochemical changes in the brain and body that differ from other psychiatric disorders such as depression. Individuals diagnosed with PTSD respond more strongly to a dexamethasone suppression test than individuals diagnosed with clinical depression. • The dexamethasone suppression test is designed to diagnose and differentiate among the various hypercortisol states. • Given the strong cortisol suppression to dexamethasone in PTSD, HPA axis abnormalities are likely due to the strong negative feedback inhibition of cortisol as a result of an increased sensitivity of the glucocorticoid receptors.

17. HPA Axis and PTSD • The HPA axis activates the LC-noradrenergic system which is implicated in the over consolidation of memories that occurs in the aftermath of trauma. This overconsolidation increases the likelihood of developing PTSD. • The locus coeruleus (LC) is the principal site for brain synthesis of norepinephrine which plays a role in regulating the HPA axis. • High levels of cortisol reduces noradrenergic activity. Due to the lower levels of cortisol associated with PTSD, it is proposed that individuals with PTSD fail to regulate the increased noradrenergic response to traumatic stress. It is thought that the intrusive memories and conditioned fear responses to associated triggers is a result of this response.

18. HPA Axis and PTSD • Low cortisol levels may predispose individuals to PTSD: Following war trauma, Swedish soldiers serving in Bosnia and Herzegovina with low pre-service salivary cortisol levels had a higher risk of reacting with PTSD symptoms, following war trauma, than soldiers with normal pre-service levels. • Because cortisol is normally important in restoring homeostasis after the stress response, it is thought that trauma survivors with low cortisol experience a longer and more distressing response, setting the stage for PTSD.

19. Treatment of PTSD Psychobiological treatments have shown success, especially with cortisol. Psychobiological treatments target biological changes that occur after a traumatic event. They also attempt to chemically alter learning or memory formation. Cortisol treatments after a traumatic event have found success in mitigating later diagnosis of PTSD. As discussed earlier, cortisol is often lower in individuals who are at risk of PTSD after a traumatic event than their counterparts. Increasing cortisol levels to normal has been shown to reduce arousal post event as well prevent glucocorticoid receptor upregulation.

20. HPA axis and Mood Disorders -The HPA axis is involved in the neurobiology of mood disorders such as anxiety disorder, bipolar disorder, major depressive disorder, etc. -HPA dysregulation can lead to severe mood disorders -increased number of CRH and AVP neurons in PVN -hypersecretion of CRH and AVP -increased cortisol levels in plasma, urine, cerebrospinal fluid and saliva -exaggerated cortisol responses to ACTH -enlarged hypothalamus, pituitary and adrenal glands

21. HPA axis and Mood Disorders -HPA dysfunctions can occur from early adversity, ongoing stress, or genetics -CRH expressing neurons are seen in higher numbers in hypothalamus of patients with mood disorders, which can induce symptoms of anxiety and depression -impaired function or lower number of GRs causes HPA hyperactivity, impaired negative feedback regulation and depression like behaviour

22. HPA axis and Mood Disorders -Video on anxiety, stress and HPA axis http://www.youtube.com/watch?v=gC33G27cQEs

23. HPA axis Dysregulation Consequences -Increase of cortisol results in reduced production and expression of BDNF, which cause depressive symptoms and cognitive impairment -Raised levels of corticosteroids impair cognition -Impaired executive performance in bipolar disorder patients

24. Bipolar Disorder -A mood disorder in which individuals experience episodes of mania and depression -There are different levels of mania, which cause different actions of the individual -The severity of the episode depends on the degree of neuroendocrine alteration -The HPA axis dysfunction is trait marker in bipolar disorder and can be indicative of core pathophysiological process

25. Bipolar disorder and Cortisol -Anxiety, insomnia and intensity of depression are correlated with cortisol response -Dysregulation of ACTH and cortisol response after CRH stimulation -Changes in CRH levels appear before manic symptoms -Abnormal DST results found during depressive episodes -Reduced pituitary volume causing pituitary hypoactivity

26. Cognitive Deficits -Hypersecretion of CRH causes hypercortisolemia due to GR abnormalities -Chronic administration of glucocorticoids impairs learning and memory -High levels of cortisol in hippocampus can produce atrophy of neurons -Number of manic episodes predict cognitive dysfunction -Higher ACTH and cortisol levels before mania shows that hypercortisolemia leads to cognitive problems

27. Treatment -Amitriptyline, paroxetine or tianeptine normalizes HPA axis to help with depressive symptoms -Antidepressants lead to gradual reinstatement of appropriate glucocorticoid receptor function -Antagonism of GR's seems to be the future therapeutic strategy for mood disorders

28. Research Article #1 • "Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder" • British Journal of Psychiatry • The purpose of the study was to test the hypothesis that HPA axis dysfunction persists in patients in remission from bipolar disorder • The HPA axis function, as variously measured by the responses to the combined dexamethasone/corticotrophin-releasing hormone (dex/CRH) test, the dexamethasone suppression test (DST) and the basal cortisol levels, has been reported to be abnormal in bipolar disorder • These tests are designed to diagnose and differentiate among hypercortisol states • Salivary cortisol levels and the plasma cortisol response to the DST and dex/CRH test were examined

29. Participants • 53 of the participants were diagnosed with bipolar disorder and were recruited from out-patient clinics in secondary care in the north-east of England (age range 23-62 years old) • 27 of those patients fulfilled stringent criteria for remission • 28 of the participants were healthy individuals with no sign of mental illness; confirmed healthy by medical examination (age range 24-60 years old)

30. Results • Patients with bipolar disorder demonstrated an enhanced cortisol response to the dex/CRH test compared with the control (healthy) participants. This response did not differ significantly between the remitted and non-remitted patients • The dex/CRH test is abnormal in both remitted and non-remitted patients with bipolar disorder; the measure of the HPA axis dysfunction is a potential trait marker in bipolar disorder and possibly indicative of the core pathophysiological process in this illness

31. Results (cont.) • The HPA axis function was abnormal in patients with bipolar disorder • The degree of abnormality is equal in remitted and non-remitted patients • Abnormal function of the HPA axis may confer vulnerability to bipolar disorder • Suggests that the HPA axis dysfunction may be involved in the disease process underlying bipolar disorder

32. Research Article #2 • "Regulation of hypothalamic-pituitary-adrenal activity in response to cognitive therapy in patients with generalized anxiety disorder" • Cognitive, Affective, and Behavioral Neuroscience Journal • The aim of this study was to evaluate the efficacy of cognitive therapy (CT) in the treatment of generalized anxiety disorder (GAD). In order to assess psychological and biological changes, the hypothalamic-pituitary-adrenal (HPA) axis function was determined through assessment of circulating cortisol levels • The normal activity of the HPA axis becomes altered during chronic stress • This results in a sustained increase of cortisol levels

33. Participants • The study subjects were patients admitted to the Stress Research Program, developed by the Department of Psychiatry and Neurosciences at Maimonides University • All the patients included met the DSM-IV criteria for GAD, and their severity of anxiety-related symptoms was assessed according to the Hamilton Anxiety Rating Scale • Total of 20 outpatients recruited, 17 of these completing the treatment (8 males and 9 females, 24-58 years of age). From the initial 20 outpatients, 3 (1 male and 2 females) additionally received antidepressants and were excluded from the protocol. A group of 8 volunteers (4 males and 4 females) recruited among outpatients from other departments also met DSM-IV criteria for GAD but did not receive any psychotherapeutic or psychopharmacologic treatment during the time of the study and did not meet any of the exclusion criteria (control group)

34. Methods • The patients began treatments with CT as soon as they were interviewed and diagnosed, receiving one 45 min individual therapy session, once a week during 24 weeks, up to a maximum of 24 sessions • Two blood samples were drawn from each participant and two additional blood samples were drawn after the completion of their treatment

35. Results • CT could provide a potential strategy not only to successfully treat chronic anxiety disorders but also to prevent the development of more severe conditions, such as depression, also associated with the dysregulation of the HPA axis • It has been shown that patients with mood and anxiety disorders often present dysregulation of the HPA axis, which may be reflected in a sustained increase of cortisol levels • This hyperactivation, with resulting hypercortisolism, has been associated with different clinical conditions, such as mood and anxiety disorders • The hypothesis raised in the study presented is in line with the notion that uncontrollable situations of distress may be associated with a dysregulation of the HPA axis

36. Multiple Choice Questions 1) The hypothalamus controls secretion of which of the following endocrine glands? A.Thyroid B.Pituitary C.Gonads D.Pancreas 2) HPA axis dysregulation can lead to severe mood disorders, what is NOT a HPA axis impairment? A. Increased number of CRH and AVP neurons B. Increased cortisol levels C. Enlarged hypothalamus, pituitary and adrenal glands D. All of the above are HPA axis impairments 3) What structure is a part of the HPA axis? A. Hypothalamus B. Pituitary Gland C. Adrenal Cortex D. All ofthe above

37. Multiple Choice Questions 4) Which hormone is observed at low levels in patients diagnosed with PTSD? A. norepinephrine B. acetylcholine C. cortisol D. vasopressin 5) Under what conditions does the HPA axis function abnormally? A. chronic stress B. bipolar disorder C. depression D. all of the above