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Stress And The Human Body

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Significance of the Course within the Program

The outcomes of Trident’s General Education courses can be found at: at http://www.trident.edu/university-catalog-student-hand-book.

Students are expected to be able to:

  1. Apply methods for using resources.
  2. Demonstrate effective written communication skills.
  3. Work effectively in collaboration with others.
  4. Apply ethical practice to decision making.
  5. Assess real-world situations in order to make appropriate decisions.
  6. Analyze the impact of human expressions on culture.

This course will address the following General Education outcomes, either implicitly or explicitly:

  1. Apply methods for using resources.
  2. Demonstrate effective written communications skills.
  3. Work effectively in collaboration with others.
  4. Assess real-world situations in order to make appropriate decisions.

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Course Overview

In this course you will learn the basic anatomy and physiology of the human body systems by examining the effects of the stress response on the nervous, immune, cardiovascular, digestive, urinary, and reproductive systems. You will also learn about the general levels of organization of life, the steps of the Scientific Method, and basic research and writing techniques. The course will follow this general outline:

Module 1: Stress and the Neuroendocrine Response

  • Defining and Contrasting Acute and Chronic Stress
  • Acute Stress and the Sympathetic Response (Nervous System)
  • Chronic Stress and Cortisol (Neuroendocrine)
  • Developing Resilience to Stress

Module 2: Chronic Stress and Behavioral Response

  • The HPA Axis and Cortisol
  • Cortisol and the Brain
  • Neuroscience of Depression, PTSD, and Common Mood Disorders

Module 3: Stress and the Immune Response

  • Immunity and the Immune Response
  • Effects of Chronic Stress and Cortisol on the Immune System
  • Effects of the Immune Response on the Brain
  • The Scientific Method

Module 4: Stress and the Cardiovascular and Digestive Systems

  • Blood Pressure Regulation
  • BP, Heart Rate, and the Sympathetic Response
  • Cortisol, Obesity, and Heart Disease

Module 5: Stress Effects on the Excretory and Reproductive Systems

  • Water Balance, BP, and Acute Stress
  • Competition and Population Dynamics
  • Cortisol and the Reproductive System

Module 6: ReflectionPrivacy Policy | Contact

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Learning Outcomes

Upon successful completion of this course, the student will be able to satisfy the following outcomes:

  • Module 1
    • Define acute and chronic stress and identify the differences in the response pathway for each.
    • Identify the anatomy and physiology of the parasympathetic and sympathetic divisions of the nervous system.
    • Identify the components of the HPA axis and neuroendocrine response to stress.
  • Module 2
    • Identify the release of cortisol in response to the HPA axis.
    • Examine the effects of cortisol on regions of the brain.
    • Identify the regions of the brain and the neuronal pathways related to the neurobiology of depression, PTSD, and the stress response.
  • Module 3
    • Examine the basics of immunity and the immune response.
    • Identify the effects of chronic stress and cortisol on the inflammatory response.
    • Apply the scientific method to investigating current theories of stress-related pathologies.
  • Module 4
    • Identify the physiology of blood pressure regulation.
    • Identify the effect of the sympathetic division of the nervous system on BP and heart rate.
    • Relate the effects of cortisol on the cardiovascular and digestive systems to the etiology of heart disease, hypertension, and diabetes.
  • Module 5
    • Identify mechanisms of water balance and blood pressure regulation.
    • Examine the influence of cortisol on the reproductive system.
  • Module 6
    • Reflect upon and integrate course concepts.

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Course Materials/Bibliography

Note: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.

Module 1

Pearson Learning Solutions: The Animal Cell. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=4589

Pearson Learning Solutions: Organization of Life. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=4652

Pearson Learning Solutions: Introductory Anatomy and Physiology and Basic Chemistry. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8746

Pearson Learning Solutions: Nervous System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10030

Pearson Learning Solutions: Endocrine System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7049

Pearson Learning Solutions: Short- and Long-Term Stress Responses. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5824

Pearson Learning Solutions: Sympathetic and Parasympathetic Divisions of the Nervous System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10056

Understanding the Stress Response. Harvard Health Publications. Harvard University. 2014. Accessed on August 16, 2014, at http://www.health.harvard.edu/newsletters/Harvard_Mental_Health_Letter/2011/ March/understanding-the-stress-response?print=1

Pearson Learning Solutions: Neuronal signalling. Pearson Higher Education, 2014. Accessed on August 14, 2014, http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5530

Pearson Learning Solutions: Synapses. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5527

Pearson Learning Solutions: Axon. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5529

Pearson Learning Solutions: Synapses and neurotransmitters. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5538

Stress Management. Mayo Health Clinic. Accessed on August 16, 2014, at http://www.mayoclinic.org/healthy-living/stress-management/in-depth/stress/art-20046037?pg=2

How does the brain handle long-term stress? Long Term Stress and the Brain. BrainFacts.org. 2012. Accessed on August 16, 2014, at http://www.brainfacts.org/about-neuroscience/ask-an-expert/articles/2012/long-term-stress-and-the-brain/

Module 2

Pearson Learning Solutions: Short- and Long-Term Stress. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5824

Pearson Learning Solutions: Biochemistry, Secretion, and Transport of Hormones. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7058

Pearson Learning Solutions: Endocrine Signaling. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5806

Pearson Learning Solutions: Steroid Hormone Action. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5815

Pearson Learning Solutions: Adrenal Glands. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5819

Pearson Learning Solutions: Hormonal Feedback Loops. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8198

“Mapping the Brain.” http://www.brainfacts.org/brain-basics/neuroanatomy/articles/2012/mapping-the-brain/

The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis. http://dujs.dartmouth.edu/fall-2010/the-physiology-of-stress-cortisol-and-the-hypothalamic-pituitary-adrenal-axis#.U-aGCONdVyw

Delaney, Eileen, PhD. The Relationship between Traumatic Stress, PTSD and Cortisol. Naval Center for Combat & Operational Stress Control.

The Amygdala and Its Allies. Accessed on August 14, 2014, at http://thebrain.mcgill.ca/flash/d/d_04/d_04_cr/d_04_cr_peu/d_04_cr_peu.html

The Amygdala and Its Allies: Several other structures in the brain. Accessed on August 14, 2014, at http://thebrain.mcgill.ca/flash/i/i_04/i_04_cr/i_04_cr_peu/i_04_cr_peu.html

Symptoms, Treatments, and Causes of Depression. Accessed on August 18, 2014, at http://thebrain.mcgill.ca/flash/a/a_08/a_08_p/a_08_p_dep/a_08_p_dep.html

Greenberg, M. How to Prevent Stress from Shrinking Your Brain. Psychology Today. http://www.psychologytoday.com/blog/the-mindful-self-express/201208/how-prevent-stress-shrinking-your-brain

Stress Effects on Structure and Function of Hippocampus. The Rockefeller University. Accessed on August 18, 2014, at http://lab.rockefeller.edu/mcewen/stresshippo

Module 3

Pearson Learning Solutions: Lymphatic and immune systems. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7101

Pearson Learning Solutions: Immune Response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5420

Pearson Learning Solutions: Primary immune response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8613

Pearson Learning Solutions: Naïve T and B cells. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8615

Pearson Learning Solutions: Antibodies. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8611

Pearson Learning Solutions: Antigen Binding. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8612

Pearson Learning Solutions: Inflammatory Mediators. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8631

Pearson Learning Solutions: Inflammatory Response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8622

Pearson Learning Solutions: Complement System. Pearson Higher Education, 2014. Accessed on August 14, 2014, http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8600

Hovhannisyan,L.P. et al. Alterations in the complement cascade in post-traumatic stress disorder. Allergy Asthma Clin Immunol. 2010; 6(1): 3. Accessed on August 18, 2014, at www.ncbi.nlm.nih.gov/pmc/articles/PMC2834673/

Pearson Learning Solutions: Scientific method. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10647

Pearson Learning Solutions: Scientific Method Diagram. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5624

Module 4

Pearson Learning Solutions: Cardiovascular system. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8037

Pearson Learning Solutions: Factors that Affect Blood Pressure (BP). Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10472

Pearson Learning Solutions: Peripheral Resistance. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10473

Pearson Learning Solutions: Pathway of Depolarization. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10486

Pearson Learning Solutions: Pathway of Depolarization EKG. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10470

Pearson Learning Solutions: Vasoconstriction. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10445

Pearson Learning Solutions: Digestive system. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7098

Pearson Learning Solutions: Hormonal Feedback Loops. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8198

Pearson Learning Solutions: Heart Rate. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10491

Pearson Learning Solutions: Stress effects on the heart. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7472

American Heart Association. Stress and Blood Pressure. Accessed on August 14, 2014, at http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/Prevention TreatmentofHighBloodPressure/Stress-and-Blood-Pressure_UCM_301883_Article.jsp#mainContent

Gasperin, D. et al. Effect of psychological stress on blood pressure increase: a meta-analysis of cohort studies. Cad. Saúde Pública, Rio de Janeiro, 2009. 25(4):715-726.

Pearson Learning Solutions: Regulating blood sugar levels. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6822

Pearson Learning Solutions: Diabetes in America. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6271

Greenberg, M. Ph.D. The Mindful Self-Express Why We Gain Weight When We’re Stressed—And How Not To. Psychology Today. August 28, 2013 http://m.psychologytoday.com/blog/the-mindful-self-express/201308/why-we-gain-weight-when-we-re-stressed-and-how-not

Maglione-Garves, C.A., Kravitz, L., and Schneider, S. Cortisol Connection: Tips on Managing Stress and Weight. Accessed on August 18, 2014, at http://www.unm.edu/~lkravitz/Article%20folder/stresscortisol.html

The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis. Dartmouth Undergraduate Journal of Science. 2010. Accessed on August 18, 2014, at http://dujs.dartmouth.edu/fall-2010/the-physiology-of-stress-cortisol-and-the-hypothalamic-pituitary-adrenal-axis#.U-zmk-NdVyw

Module 5

Pearson Learning Solutions: Movement of Fluids in the Body. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11140

Pearson Learning Solutions: Urinary System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6564

Pearson Learning Solutions: Nephron. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6899

Pearson Learning Solutions: Filtration through the Renal Capsule. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6885

Pearson Learning Solutions: Filtration at the Nephron. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11103

Pearson Learning Solutions: Resorption. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11109

Pearson Learning Solutions: Secretion. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11110

Pearson Learning Solutions: Juxtaglomerular Apparatus. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6886

Pearson Learning Solutions: Dehydration Response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11128

Pearson Learning Solutions: Female Reproductive System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7280

Pearson Learning Solutions: Male Reproductive System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7282

Sanders, R. Stress puts double whammy on reproductive system. UC Berkeley News. 15 June 2009.

Kalantaridou, N.S., et al. Stress and the female reproductive system. Journal of Reproductive Immunology. 2004.62:61-68Privacy Policy | Contact

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Module 1 – Home

Stress and the Neuroendocrine Response

Modular Learning Outcomes

Upon successful completion of this module, the student will be able to satisfy the following outcomes:

  • Case
    • Identify the anatomy and physiology of the parasympathetic and sympathetic divisions of the nervous system.
    • Contrast the physiology of the stress response for acute and chronic stressors.
    • Identify stress management techniques.
  • SLP
    • Examine the components of neuronal communication.
    • Examine plasticity in neuronal circuits.
    • Identify the role of the hippocampus in stress resilience and negative feedback.
  • Discussion
    • Identify stressors and mechanisms of stress management in your life.

Module Overview

[Note: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.]

We begin our investigation of the effects of stress on the human body by defining some of the basic principles of biology and human anatomy and physiology. As you already know, we humans are alive! While this seems like an obvious statement, there are some distinct characteristics that scientists use to differentiate living from non-living. As you view the characteristics that define organisms as living, notice that our bodies are designed to accomplish the tasks associated with being alive.

For example, we maintain organization at the smallest level within the cell, the smallest unit of life. This requires an input of energy, which we must obtain from our environment and convert to usable forms. Our metabolism determines the rate at which we convert the energy obtained from our food. Our cells cooperate as tissues, tissues cooperate to form organs, and organs work together in organ systems to maintain the overall organization of the body, and keep the body in a state of homeostasis, or balance. Organisms that acquire resources efficiently enough to maintain homeostasis will be successful enough to make it to reproductive age, and potentially pass these successful genes onto the next generation by reproducing.

Now complete this introductory Anatomy and Physiology tutorial that covers the basic chemistry and organization of the body, before continuing on in your reading. You will be required to refer back to this tutorial in your Case and SLP assignments, so be sure to take some notes as you work through it.

The first two modules of this course focus on two of the body’s systems responsible for maintaining homeostasis, the nervous and endocrine systems. These systems are also the first to respond to stress. Within the nervous system, cells called neurons collect information from the body and relay it to the brain in the form of electric impulses. Carefully study the organs labeled in the diagram below. These are important components of the brain that integrate the information related to the stress response. The cerebral cortex, thalamus, hypothalamus, and pituitary glands are all parts of the brain responsible for processing these incoming nervous signals. As these regions communicate with each other and gather information from sensory processing regions of the brain, the signals are integrated and a decision is made about how to respond. The executive decision is sent to effector organs that include many systems of the body. In response to stress, the outgoing, or efferent, signals can be sent directly to the organs that need to respond: the heart may be stimulated to increase heart rate, for example. The efferent signal will also be sent to an endocrine gland, the adrenal glands, to signal release of the hormones epinephrine and norepinephrine. These are chemical signals associated with an “adrenaline rush” that travel through the blood stream to target organs. These signals, like the direct signals delivered by efferent neurons, will stimulate or inhibit the organs involved in the “fight or flight” response that is elicited by stressful stimuli.

Glands

Stresses can be divided into two different types: acute and chronic stress. Both elicit a response from the endocrine system by signaling the release of hormones that will travel throughout the body to signal organs to respond to the wide variety of stressful stimuli we encounter every day.Privacy Policy | Contact

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Module 1 – Background

Stress and the Neuroendocrine Response

Note: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.

Pearson Learning Solutions: The Animal Cell. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=4589

Pearson Learning Solutions: Organization of Life. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=4652

Pearson Learning Solutions: Introductory Anatomy and Physiology and Basic Chemistry. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8746

Pearson Learning Solutions: Nervous System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10030

Pearson Learning Solutions: Endocrine System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7049

Pearson Learning Solutions: Short- and Long-Term Stress Responses. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5824

Pearson Learning Solutions: Sympathetic and Parasympathetic Divisions of the Nervous System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10056

Understanding the Stress Response. Harvard Health Publications. Harvard University. 2014. Accessed on August 16, 2014, at http://www.health.harvard.edu/newsletters/Harvard_Mental_Health_Letter/2011/March/understanding-the-stress-response?print=1

Pearson Learning Solutions: Neuronal signalling. Pearson Higher Education, 2014. Accessed on August 14, 2014, http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5530

Pearson Learning Solutions: Synapses. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5527

Pearson Learning Solutions: Axon. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5529

Pearson Learning Solutions: Synapses and neurotransmitters. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5538

Stress Management. Mayo Health Clinic. Accessed on August 16, 2014, at

http://www.mayoclinic.org/healthy-living/stress-management/in-depth/stress/art-20046037?pg=2

How does the brain handle long-term stress? Long Term Stress and the Brain. BrainFacts.org. 2012. Accessed on August 16, 2014, at http://www.brainfacts.org/about-neuroscience/ask-an-expert/articles/2012/long-term-stress-and-the-brain/Privacy Policy | Contact

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8/9/2014 Understanding the Stress Response – Harvard Health Publications

http://www.health.harvard.edu/newsletters/Harvard_Mental_Health_Letter/2011/March/understanding-the-stress-response?print=1 1/4

Understanding the stress response

Chronic activation of this survival mechanism impairs health.

For two years in a row, the annual stress survey commissioned by the American Psychological Association has found that about 25% of Americans are experiencing high levels of stress (rating their stress level as 8 or more on a 10-point scale), while another 50% report moderate levels of stress (a score of 4 to 7). Perhaps not surprising, given continuing economic instability in this country and abroad, concerns about money, work, and the economy rank as the top sources of stress for Americans.

Stress is unpleasant, even when it is transient. A stressful situation — whether something environmental, such as a looming work deadline, or psychological, such as persistent worry about losing a job — can trigger a cascade of stress hormones that produce well-orchestrated physiological changes. A stressful incident can make the heart pound and breathing quicken. Muscles tense and beads of sweat appear.

This combination of reactions to stress is also known as the “fight-or-flight” response because it evolved as a survival mechanism, enabling people and other mammals to react quickly to life-threatening situations. The carefully orchestrated yet near-instantaneous sequence of hormonal changes and physiological responses helps someone to fight the threat off or flee to safety. Unfortunately, the body can also overreact to stressors that are not life-threatening, such as traffic jams, work pressure, and family difficulties.

Over the years, researchers have learned not only how and why these reactions occur, but have also gained insight into the long-term effects stress has on physical and psychological health. Over time, repeated activation of the stress response takes a toll on the body. Research suggests that prolonged stress contributes to high blood pressure, promotes the formation of artery-clogging deposits, and causes brain changes that may contribute to anxiety, depression, and addiction. More preliminary research suggests that chronic stress may also contribute to obesity, both through direct mechanisms (causing people to eat more) or indirectly (decreasing sleep and exercise).

Sounding the alarm

The stress response begins in the brain (see illustration). When someone confronts an oncoming car or other danger, the eyes or ears (or both) send the information to the amygdala, an area of the brain that contributes to emotional processing. The amygdala interprets the images and sounds. When it perceives danger, it instantly sends a distress signal to the hypothalamus.

Command centerhttp://www.health.harvard.edu/

8/9/2014 Understanding the Stress Response – Harvard Health Publications

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When someone experiences a stressful event, the amygdala, an area of the brain that contributes to emotional processing, sends a distress signal to the hypothalamus. This area of the brain functions like a command center, communicating with the rest of the body through the nervous system so that the person has the energy to fight or flee.

The hypothalamus is a bit like a command center. This area of the brain communicates with the rest of the body through the autonomic nervous system, which controls such involuntary body functions as breathing, blood pressure, heartbeat, and the dilation or constriction of key blood vessels and small airways in the lungs called bronchioles. The autonomic nervous system has two components, the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system functions like a gas pedal in a car. It triggers the fight-or-flight response, providing the body with a burst of energy so that it can respond to perceived dangers. The parasympathetic nervous system acts like a brake. It promotes the “rest and digest” response that calms the body down after the danger has passed.

After the amygdala sends a distress signal, the hypothalamus activates the sympathetic nervous system by sending signals through the autonomic nerves to the adrenal glands. These glands respond by pumping the hormone epinephrine (also known as adrenaline) into the bloodstream. As epinephrine circulates through the body, it brings on a number of physiological changes. The heart beats faster than normal, pushing blood to the muscles, heart, and other vital organs. Pulse rate and blood pressure go up. The person undergoing these changes also starts to breathe more rapidly. Small airways in the lungs open wide. This way, the lungs can take in as much oxygen as possible with each breath. Extra oxygen is sent to the brain, increasing alertness. Sight, hearing, and other senses become sharper. Meanwhile, epinephrine triggers the release of blood sugar (glucose) and fats from temporary storage sites in the body. These nutrients flood into the bloodstream, supplying energy to all parts of the body.

All of these changes happen so quickly that people aren’t aware of them. In fact, the wiring is so efficient that the amygdala and hypothalamus start this cascade even before the brain’s visual centers have had a chance to fully process what is happening. That’s why people are able to jump out of the path of an oncoming car even before they think about what they are doing.

As the initial surge of epinephrine subsides, the hypothalamus activates the second component of the stress response system — known as the HPA axis. This network consists of the hypothalamus, the pituitary gland, and the adrenal glands.

The HPA axis relies on a series of hormonal signals to keep the sympathetic nervous system — the “gas pedal” — pressed down. If the brain continues to perceive something as dangerous, the hypothalamus releases corticotropin-releasing hormone (CRH), which travels to the pituitary gland, triggering the release of adrenocorticotropic hormone (ACTH). This hormone travels to the adrenal glands, prompting them to release

8/9/2014 Understanding the Stress Response – Harvard Health Publications

http://www.health.harvard.edu/newsletters/Harvard_Mental_Health_Letter/2011/March/understanding-the-stress-response?print=1 3/4

cortisol. The body thus stays revved up and on high alert. When the threat passes, cortisol levels fall. The parasympathetic nervous system — the “brake” — then dampens the stress response.

Techniques to counter stress

The findings of the national survey mentioned earlier support what mental health clinicians experience in their own practices — many people are unable to find a way to put the brakes on stress. Chronic low-level stress keeps the HPA axis activated, much like a motor that is idling too high for too long. After a while, this has an effect on the body that contributes to the health problems associated with chronic stress.

Persistent epinephrine surges can damage blood vessels and arteries, increasing blood pressure and raising risk of heart attacks or strokes. Elevated cortisol levels create physiological changes that help to replenish the body’s energy stores that are depleted during the stress response. But they inadvertently contribute to the buildup of fat tissue and to weight gain. For example, cortisol increases appetite, so that people will want to eat more to obtain extra energy. It also increases storage of unused nutrients as fat.

Fortunately, people can learn techniques to counter the stress response.

Relaxation response. Dr. Herbert Benson, director emeritus of the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, has devoted much of his career to learning how people can counter the stress response by using a combination of approaches that elicit the relaxation response. These include deep abdominal breathing, focus on a soothing word (such as peace or calm), visualization of tranquil scenes, repetitive prayer, yoga, and tai chi.

Most of the research using objective measures to evaluate how effective the relaxation response is at countering stress have been conducted in people with hypertension and other forms of heart disease. Those results suggest the technique may be worth trying — although for most people it is not a cure-all. For example, researchers at Massachusetts General Hospital conducted a double-blind, randomized controlled trial of 122 patients with hypertension, ages 55 and older, in which half were assigned to relaxation response training and the other half to a control group that received information about blood pressure control. After eight weeks, 34 of the people who practiced the relaxation response — a little more than half — had achieved a systolic blood pressure reduction of more than 5 mm Hg, and were therefore eligible for the next phase of the study, in which they could reduce levels of blood pressure medication they were taking. During that second phase, 50% were able to eliminate at least one blood pressure medication — significantly more than in the control group, where only 19% eliminated their medication.

Physical activity. People can use exercise to stifle the buildup of stress in several ways. Exercise, such as taking a brisk walk shortly after feeling stressed, not only deepens breathing but also helps relieve muscle tension. Movement therapies such as yoga, tai chi, and qi gong combine fluid movements with deep breathing and mental focus, all of which can induce calm.

Social support. Confidants, friends, acquaintances, co-workers, relatives, spouses, and companions all provide a life-enhancing social net — and may increase longevity. It’s not clear why, but the buffering theory holds that people who enjoy close relationships with family and friends receive emotional support that indirectly helps to sustain them at times of stress and crisis.

Dusek JA, et al. “Stress Management Versus Lifestyle Modification on Systolic Hypertension and Medication Elimination: A Randomized Trial,” Journal of Alternative and Complementary Medicine (March 2008): Vol. 14, No. 2, pp. 129–38.

Holt-Lunstad J, et al. “Social Relationships and Mortality Risk: A Meta-Analytic Review,” PLoS Medicine (July 27, 2010): Vol. 7, No. 7, electronic publication.

McEwen B, et al. The End of Stress as We Know It (The Dana Press, 2002).

For more references, please see www.health.harvard.edu/mentalextra (/mentalextra).http://www.health.harvard.edu/mentalextra

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Module 1 – Case

Stress and the Neuroendocrine Response

STOP!!! Review the text and diagram on the Home page and the introductory Anatomy and Physiology tutorial before proceeding with this assignment!

Case Assignment

Now study this diagram showing how the body responds to stressful stimuli. Notice that short-term stress follows one signaling pathway that begins in the brain, travels out the spinal cord, and directly to the adrenal glands. Many organs of the body will receive direct stress response messages using this pathway as well. When the adrenal glands receive the signal from this pathway, they release a stress hormone that signals many systems in the body to prepare to either run away from the stressor (such as a predator or an oncoming vehicle, for example), or fight. The part of the nervous system that activates this response to acute stress is called the sympathetic nervous system. After the stressful stimulus has passed, the parasympathetic (nicknamed the “rest and digest” response) calms the nervous system and restores the normal function of the body systems, maintaining homeostasis.

The Sympathetic vs. Parasympathetic Nervous Systems

These two divisions of the nervous system counteract each other to allow the body to receive the resources it needs to respond to a life-threatening situation (more glucose to the brain to enhance thinking ability, more oxygen and sugars to the muscles to run, etc.), and then return to a relaxed state. As you saw in the diagram, the sympathetic response begins when a stressful situation is detected by your sensory nerves, which make up the peripheral nervous system, or PNS. The sensory nerve endings can deliver this message directly to the brain through cranial nerves, which gather the information we need to give us the senses of smell, sight, hearing, and taste. Stress stimuli can also be detected by peripheral nerve endings throughout the body and delivered to the brain via the spinal cord. The brain and the spinal cord make up the central nervous system, or CNS.

View this diagram to review the anatomy of the sympathetic and parasympathetic nervous systems.

Notice that the “rest and digest” (parasympathetic) message is delivered through cranial nerves that originate in the brain stem, and sacral nerves that originate in the sacrum at the end of the spinal cord. The “fight or flight” (sympathetic) response originates from the spinal cord. These nerve impulses are delivered by the CNS to the effector organs responsible for reacting to the situation by either simulating the organ to take action, or calming (inhibiting) the organ to return homeostasis. In this situation, the nervous system sends a signal to the endocrine system to handle acute, or short-term stress.

When the body is faced with long-term, or chronic stress, the endocrine system predominantly responds by releasing hormones such as cortisol. You will learn more about cortisol in the next module.

Read Understanding the Stress Response in Harvard Health Publications, published by the Harvard Medical School.

From your reading address the following:

  1. Define acute and chronic stress. Provide examples.
  2. What region of the brain detects stress and interprets the stimulus as dangerous? What is its function, and where does it relay the signal that conveys the danger? What format is the signal in? What is the role of the region of the brain that receives the stress alert?
  3. What is a hormone? What hormones are involved in the stress response? When are hormones released in the stress response?
  4. What is the HPA and what role does it play in the stress response?
  5. What recommendations are given to counter stress?

Assignment Expectations

Organize this assignment using subtitles that summarize each question above. For example, to answer Question 1, use the subtitle: Acute versus Chronic Stress. Answer each question under the subtitle using complete sentences that relate back to the question. Be sure to include a reference section at the end of your assignment that lists the sources that you were required to read and any additional resources you used to research your answers. Follow the format provided in the Background page.Privacy Policy | Contact

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Module 1 – SLP

Stress and the Neuroendocrine Response

As you work through this SLP assignment, you will learn more about the flexibility, or plasticity, of the brain. You have learned about how the spinal nerves can deliver messages directly to effector organs from the CNS through peripheral nerves that branch off of the spinal cord. These nerves are collections of neurons bundled in connective tissue. Neurons also communicate with each other within the CNS and establish circuits and neuronal pathways.

First take some time to work through these tutorials about how neurons communicate:

  1. Neurons communicate with each other
  2. Neurons communicate at synapses
  3. Communication is delivered via the axon
  4. Synapses and neurotransmitters: Be sure to click on “Presynaptic neuron,” “synaptic cleft,” and “postsynaptic neuron.”

Throughout life, the connections between neurons in the brain develop and change according to the genetic foundations that the individual inherits from the parents, and the environmental influences to which the individual must respond. For example, the abundance of one type of neuron over another, and the neurotransmitter that each produces can be predetermined by the DNA an individual inherits. However, an individual who is exposed to chronic stress during developmental years may reinforce some response pathways more than individuals who do not experience the same patterns of stress. These points are summarized and explained further in this article “Stress Management,” provided by the Mayo Clinic. Read this brief article before continuing to the requirements for this SLP.

Continue your reading on how the brain handles stress and the idea of plasticity at BrainFacts.org, a public information initiative of the Society for Neuroscience, The Kavli Foundation, and Gatsby. Read the article, “How does the brain handle long-term stress?” and follow the link to the article, “Effects of Stress on the Developing Brain” in the right-hand column of links provided on this page. Address these questions in paragraph format to complete the SLP assignment for Module 1:

  1. What is a neurotransmitter and what is its function?
  2. What neurotransmitter is mentioned in the article, “How does the brain handle long-term stress?”
  3. How is short-term stress described in this article?
  4. Do a little independent research on the hippocampus. Where is it located in the brain? Briefly describe its function and neurogenesis. Insert a labeled picture into your assignment illustrating its location.
  5. How is long-term stress differentiated from short-term stress in this article? What brain region is involved in this comparison and what is its general function? Insert a labeled picture of this region into your assignment illustrating its location in the brain.
  6. After reading the article “Effects of Stress on the Developing Brain,” explain the implications of chronic stress on the brain and the rest of the body reported by the authors. What examples of chronic stressors are included?
  7. What components of parental care are described as being important determinants of brain development in this article? What genetic influences are described as relevant to the ability to handle stressful environments?

SLP Assignment Expectations

Organize this assignment using subtitles related to the content for each question. Answer each question under the subtitle using complete sentences that relate back to the question. Be sure to include a references section at the end of your assignment that lists the sources that you were required to read and any additional resources you used to research your answers. Follow the format provided in the Background page.Privacy Policy | Contact

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Module 1 – Outcomes

Stress and the Neuroendocrine Response

  • Module
    • Define acute and chronic stress and identify the differences in the response pathway for each.
    • Identify the anatomy and physiology of the parasympathetic and sympathetic divisions of the nervous system.
    • Identify the components of the HPA axis and neuroendocrine response to stress.
  • Case
    • Identify the anatomy and physiology of the parasympathetic and sympathetic divisions of the nervous system.
    • Contrast the physiology of the stress response for acute and chronic stressors.
    • Identify stress management techniques.
  • SLP
    • Examine the components of neuronal communication.
    • Examine plasticity in neuronal circuits.
    • Identify the role of the hippocampus in stress resilience and negative feedback.
  • Discussion
    • Identify stressors and mechanisms of stress management in your life.

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Module 2 – Home

Chronic Stress and Behavioral Response

Modular Learning Outcomes

Upon successful completion of this module, the student will be able to satisfy the following outcomes:

  • Case
    • Identify the molecular composition of cortisol and the signaling pathway that elicits the production and release of cortisol.
    • Investigate the cellular-, organ-, and organ system-level response to cortisol.
    • Investigate the relationship between traumatic stress, PTSD, and cortisol.
  • SLP
    • Identify sites of neurogenesis in the brain.
    • Identify effects of cortisol dysregulation on the amygdala, prefrontal cortex, and hippocampus.
  • Discussion
    • Investigate the relationship between stress and depression.

Module Overview

In Module 2 you were introduced to acute versus chronic stress, the stress response, and the role of the sympathetic and parasympathetic divisions of the nervous system in managing stress. You were also introduced to important regions of the brain involved in the interpretation and processing of stress. In this module we will focus on the effects of chronic stress, the HPA axis, and the effects of cortisol on the body.

Review the diagram from Module 1 depicting the differences in how the nervous system communicates with the endocrine system when exposed to short-term (acute) vs. long-term (chronic) stress. Notice that there is a cascade of hormones that is triggered, originating from a signal from the hypothalamus that stimulates the pituitary gland in the brain to release “stress hormones,” called glucocorticoids. An important glucocorticoid, cortisol, has been extensively studied and will be the focus of the endocrine system response in this module.

The endocrine system sends chemical signals to organs of the body to maintain homeostasis. There are three pathways by which an endocrine gland can receive a stimulus to release its chemical signal:

  1. Hormonal: hormones signal other endocrine glands to release their hormones
  2. Humoral: changes in body chemistry signal the release of hormones by an endocrine gland
  3. Neural: an electrical impulse delivered by a neuron signals hormone release

Hormones are composed of different molecules that will determine the type of response elicited in the cell. Cortisol is a steroid hormone that triggers protein production within its target cells. These proteins may compose enzymes that facilitate metabolic processes, as in blood sugar regulation by the liver. Nonsteroid proteins can stimulate reactions in the cell that influence overall cell function. Cortisol is released by the adrenal glands located above the kidney and it is classified as a type of glucocorticoid hormone, due to way it binds to its target cell. The endocrine and nervous systems are closely intertwined, highly sophisticated, messaging systems that operate through negative and positive feedback loops. This means that some signals stimulate the production of more signals in positive feedback, while other signals inhibit the propagation of future signals in a negative feedback loop. Continue your background reading on the organization of the nervous system at “Mapping the Brain.”Privacy Policy | Contact

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Module 2 – Background

Chronic Stress and Behavioral Response

Note: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.

Pearson Learning Solutions: Short- and Long-Term Stress. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5824

Pearson Learning Solutions: Biochemistry, Secretion, and Transport of Hormones. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7058

Pearson Learning Solutions: Endocrine Signaling. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5806

Pearson Learning Solutions: Steroid Hormone Action. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5815

Pearson Learning Solutions: Adrenal Glands. Pearson Higher Education, 2012. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5819

Pearson Learning Solutions: Hormonal Feedback Loops. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8198

“Mapping the Brain.” http://www.brainfacts.org/brain-basics/neuroanatomy/articles/2012/mapping-the-brain/

The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis. http://dujs.dartmouth.edu/fall-2010/the-physiology-of-stress-cortisol-and-the-hypothalamic-pituitary-adrenal-axis#.U-aGCONdVyw

Delaney, Eileen, PhD. The Relationship between Traumatic Stress, PTSD and Cortisol. Naval Center for Combat & Operational Stress Control.

The Amygdala and Its Allies. Accessed on August 14, 2014, at http://thebrain.mcgill.ca/flash/d/d_04/d_04_cr/d_04_cr_peu/d_04_cr_peu.html

The Amygdala and Its Allies: Several other structures in the brain. Accessed on August 14, 2014, at http://thebrain.mcgill.ca/flash/i/i_04/i_04_cr/i_04_cr_peu/i_04_cr_peu.html

Symptoms, Treatments, and Causes of Depression. Accessed on August 18, 2014, at http://thebrain.mcgill.ca/flash/a/a_08/a_08_p/a_08_p_dep/a_08_p_dep.html

Greenberg, M. How to Prevent Stress from Shrinking Your Brain. Psychology Today. http://www.psychologytoday.com/blog/the-mindful-self-express/201208/how-prevent-stress-shrinking-your-brain

Stress Effects on Structure and Function of Hippocampus. The Rockefeller University. Accessed on August 18, 2014, at http://lab.rockefeller.edu/mcewen/stresshippoPrivacy Policy | Contact

content/enforced/45566-ANT100-WIN2015-1/Modules/Module2/Mod2Case.html/ptsd-and-cortisol.pdf

Many researchers have studied how trauma and posttraumatic stress disorder

(PTSD) impact cortisol, a primary stress hormone. Although cortisol

dysregulation is common in the general population, PTSD appears to hasten

cortisol imbalance and its extensive consequences, making it an important area of

continued study. The following paper provides a brief review of the documented

relationship between traumatic stress and cortisol, as well as an overview of how

cortisol responds to clinical treatments targeting PTSD.

The stress response

In his seminal work, Hans Selye 1 defined stress as “the non-specific response of the

body to any demand placed upon it” and noted that the body’s reaction to stress (also

referred to as the general adaptation syndrome or the stress response) can be activated

by both actual and perceived demands.

When a stressor is identified, the hypothalamic-pituitary-adrenal (HPA) axis activates

the “fight-or-flight” response. Cortisol, released by the adrenal gland, plays a key role in

directing physiological and metabolic processes away from long-term management to

immediate survival (e.g., increases in heart rate, decreases in digestion, alterations in

immune functioning) and then works together with dehydroepiandrosterone (DHEA) to

bring the body back to a normal state 2 . For a detailed review of the stress response,

please refer to Selye 3 .

Cortisol dysregulation and its consequences

Prolonged activation of the stress response can compromise the body’s internal stability,

resulting in HPA axis dysregulation and alterations in cortisol levels. Chronic illness

and disease can then ensue due to cortisol’s impact on the immune system. Enhanced

cortisol activity suppresses cellular immunity, increasing susceptibility to infection and

The Relationship between Traumatic Stress, PTSD and Cortisol

By Eileen Delaney, PhD

Naval Center for Combat & Operational Stress Control

2

neoplasm (abnormal growth of tissue), while low cortisol levels stimulate pro-

inflammatory cytokines, which can lead to autoimmune diseases and malignancy 2 .

Endocrine disorders can be another consequence of abnormal cortisol functioning. High

levels of cortisol decrease the liver’s sensitivity to insulin (i.e., insulin resistance),

which increases glucose levels in the blood. If left untreated, high blood glucose can

lead to kidney, neurological and cardiovascular damage 4 .

Mental health and cognitive problems may also develop from cortisol dysregulation.

Hypercortisolism is associated with obsessive-compulsive disorder, panic disorder and

melancholic depression, while hypocortisolism has been linked to depressed mood,

chronic pain, sleep disturbances and fatigue 2 . Additionally, cortisol’s ability to bind to

receptors in the hippocampus (the brain region involved in memory) can impact

memory and consciousness. An over-production of cortisol can shrink and cause

atrophy of the hippocampus, leading to memory difficulties 5 . Severe hippocampal

atrophy may result in periods of dissociation 6 .

Cortisol and PTSD

It is well documented that individuals with PTSD have altered cortisol levels, yet the

direction of impairment (i.e., too high or too low) is mixed. Yehuda and colleagues 7

showed that chronic PTSD was associated with lowered cortisol activity compared to

those without a PTSD diagnosis and suggested that chronically high stress levels may

exhaust the HPA axis. Other studies have found higher cortisol activity in those with

PTSD. One research team found that compared to controls, Vietnam combat veterans

with PTSD had higher overall cortisol levels 8 . Another study documented that Croatian

combat veterans had fewer glucocorticoid receptors (receptors that cortisol binds to)

compared to healthy controls 9 , which could also contribute to higher levels of

circulating cortisol.

One study found that child abuse victims with PTSD experienced enhanced cortisol

activity in response to exposure to traumatic reminders, bringing researchers to

conclude that low levels of baseline cortisol may compensate for periods of higher

cortisol levels that accompany stress 10

. Still, some researchers have documented normal

3

cortisol levels in a sample that consisted of individuals diagnosed with PTSD from

varying types of events (e.g., childhood trauma, domestic violence, war) 11

.

Family and individual factors are important to consider when examining the relationship

between PTSD and cortisol activity. Yehuda and colleagues 12

documented lower

cortisol excretion in children of holocaust survivors with PTSD compared to healthy

controls. Further, children who had two parents with PTSD had lower levels compared

to those who only had one parent with PTSD. The authors note that the impact of

parental PTSD on the child’s cortisol level could be related to both biological

mechanisms and the environment in which the child is raised (e.g., parental neglect).

Avoidance, a hallmark symptom of PTSD, may also play a significant role in the

relationship between cortisol and PTSD. Research has shown that the engagement-

nonengagement style of coping influences cortisol levels 13,14

and that nonengagement

has been associated with low levels of cortisol 15

. These findings may explain some of

the variability in cortisol findings across PTSD populations. Those patients who avoid

and withdraw to a greater extent may have lower cortisol levels. Additionally, cortisol

levels vary throughout the day and in different situations within the same individual 16

.

Thus, times of avoidance, withdrawal and isolation may be associated with lower

cortisol levels, while re-experiencing and hyperarousal are related to enhanced cortisol

activity.

Cortisol and PTSD treatment

Given the neuroendocrine dysregulation in those with PTSD, researchers have begun to

study the impact of PTSD treatments on cortisol levels. Olff, de Vries, Guzelcan, Assies

and Gersons 17

examined cortisol response to trauma-based cognitive-behavioral therapy

(CBT) in 21 individuals with PTSD due to civilian traumas. They found that successful

treatment, assessed by the Structured Interview for PTSD (SI-PTSD) and self-report

symptom measures (i.e., Impact of Event Scale [IES], Beck Depression Inventory

[BDI]), was associated with enhanced levels of basal cortisol and DHEA at post-

treatment. However, the improvements in hormonal measures were only seen when

depression symptoms were included in the model.

4

Using a sample of 28 trauma survivors from the 9/11 attack of the World Trade Center,

Yehuda and colleagues 18

monitored individuals’ cortisol levels as they participated in

psychological treatment. Basal cortisol and PTSD severity (assessed by the

Posttraumatic Stress Symptom-Interview [PSSI] and the PTSD Symptom Scale-Self

Report [PSS-SR]) were collected before and after treatment. At pre-treatment, cortisol

indicators (5-alpha reductase activity, total glucocorticoids) were lower for those who

had higher avoidance scores but for no other symptom cluster (i.e., re-experiencing,

hyperarousal). At post-treatment, 5-alpha reductase activity was significantly correlated

with all three PTSD symptom clusters, as well as total severity scores. Overall, these

findings indicate that those who were highly avoidant showed lowered cortisol activity,

and successful treatment increased cortisol levels.

Gerardi, Rothbaum, Astin and Kelly 19

were the first researchers to use a randomized

control design when examining cortisol response to PTSD treatment. Sixty women with

PTSD were randomly assigned to prolonged exposure (PE), eye-movement

desensitization and reprocessing (EMDR) or waitlist. Measures were taken at three time

points: at baseline, immediately after session 3 (first exposure session) and immediately

after session 9 (last exposure session). Results showed that treatment response (i.e., at

least a 50 percent reduction in PTSD symptoms assessed via the Clinician-Administered

PTSD Scale [CAPS]) was associated with decreased cortisol levels. Cortisol

measurements taken immediately after exposure sessions may explain why effective

treatment was related to lower cortisol levels, whereas previous studies documented

increased cortisol in response to treatment.

Summary and future directions

Cortisol plays a key role in physical and mental well-being. Research has shown that

those with chronic PTSD often have dysregulated basal cortisol levels, yet individual

and family factors (i.e., extent of isolation, parental PTSD) may also play a role.

Investigators have begun to study the impact of PTSD treatment on cortisol activity and

have found that clinical treatments have the potential to stabilize cortisol levels.

However, a significant limitation in this line of study is the lack of prospective designs.

Since cortisol activity prior to the traumatic event is often unknown, causation cannot be

5

established. Although it is often assumed that traumatic events alter cortisol levels, it is

also possible that trauma survivors who develop PTSD had low cortisol activity before

the event, which increased their vulnerability to developing the disorder. Another

limitation is the various ways in which cortisol is assessed, making these measurements

difficult to compare without the use of meta-analytic strategies. With continued

research, further inquiry to how cortisol interacts with trauma may hold promise in

helping improve detection and treatment of PTSD and other trauma-related problems.

References:

1. Selye H. The general adaptation syndrome and diseases of adaptation. The

Journal of Clinical Endocrinology and Metabolism. 1936; 6(2):117-230.

2. Guilliams TG, Edwards L. Chronic stress and the HPA axis: Clinical assessment

and therapeutic considerations. A Review of Natural & Nutraceutical Therapies

for Clinical Practice. 2010; 9(2):1-12.

3. Selye H. Stress and the general adaptation syndrome. British Medical Journal.

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4. Lansang MC, Hustak LK. Glucocorticoid-induced diabetes and adrenal

suppression: How to detect and manage them. Cleveland Clinic Journal of

Medicine. 2011; 78(11):748-756.

5. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens, MJ, Southwick SM,

Nemeroff, CB, Charney, DS. Elevated CSF corticotropin-releasing factor

concentrations in posttraumatic stress disorder Am J Psychiatry. 1997; 154(5):

624-629.

6. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric

disorders. Archives of General Psychiatry. 2000; 57:925-935.

7. Yehuda R, Bierer LM, Schmeidler J, Aferiat DH, Breslau I, Dolan S. Low

cortisol and risk for PTSD in adult offspring of Holocaust survivors. American

Journal of Psychiatry. 2000; 157:1252–1259.

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8. Pitman R, Orr S. Twenty-four-hour urinary cortisol and catecholamine excretion

in combat-related posttraumatic stress disorder. Biological Psychiatry. 1990;

27(2):245-247.

9. Gotovac K, Sabioncello A, Rabatic S, Berki T, Dekaris D. Flow cytometric

determination of glucocorticoid receptor (GCR) expression in lymphocyte

subpopulations: Lower quantity of GCR in patients with post-traumatic stress

disorder (PTSD). Clin Exp Immunol. 2003; 131:335–339.

10. Elzinga BM, Schmahl, CG, Vermetten E, van Dyck R, Bremner JD. Higher

cortisol levels following exposure to traumatic reminders in abuse-related PTSD.

Neuropharmacology. 2003; 28:1656 – 1666.

11. Wheler GH, Brandon D, Clemons A, Riley C, Kendall J, Loriaux DL, Kinzie JD.

Cortisol production rate in posttraumatic stress disorder. The Journal of Clinical

Endocrinology and Metabolism. 2006; 91(9):3486-3489.

12. Yehuda R, Halligan SL, Bierer, LM. Cortisol levels in adult offspring of

Holocaust survivors: Relation in PTSD symptom severity in the parent and child.

Psychoneuroendocrinology. 2002; 27: 171-180.

13. Price DB, Thaler M, Mason JW. Preoperative emotional states and adrenal

cortical activity. Arch Gen Psychiatry. 1957; 77:646–56.

14. Singer MT. Engagement-involvement: a central phenomenon in

psychophysiological research. Psychosom Med. 1974; 36:1–17.

15. Mason JW, Wang S, Yehuda R, Riney S, Charney, DS, Southwick S.

Psychogenic lowering of urinary cortisol levels linked to increased emotional

numbing and a shame-depressive syndrome in combat-related posttraumatic

stress disorder. Psychosomatic Medicine. 2001; 63:387-401.

16. Weitzman ED, Fukushima D, Nogeire C, Roffwarg H, Gallagher TF, Hellman L.

Twenty-four-hour pattern of the episodic secretion of cortisol in normal subjects.

Journal of Clinical Endocrinology Metabolism. 1971; 33:14–22.

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17. Olff M, de Vries G, Guzelcan Y, Assies J, Gersons B. Changes in cortisol and

DHEA plasma levels after psychotherapy for PTSD. Psychoneuroendocrinology.

2007; 32:619-626.

18. Yehuda R, Bierer LM, Sarapass C, Makotkine L, Andrew R, Seckl J. Cortisol

metabolic predictors of response to psychotherapy for symptoms of PTSD in

survivors of the World Trade Center attacks on September 11, 2001.

Psychoneuroendocrinology. 2009: 34(9):1304-1313.

19. Gerardi M, Rothbaum BO, Astin MC, Kelly M. Cortisol response following

exposure treatment for PTSD in rape victims. Journal of Aggression,

Maltreatment, and Trauma. 2010; 19(4):349-356.

content/enforced/45566-ANT100-WIN2015-1/Modules/Module2/Mod2Case.html/Modules/Module2/Mod2Case.html

Module 2 – Case

Chronic Stress and Behavioral Response

STOP!!! BEFORE YOU PROCEED, BE YOU MUST HAVE READ THE HOME PAGE AND VIEWED ALL LINKS AND TUTORIALS!!! You will need this information to complete this Case Assignment.

Assignment Overview

Cortisol is an important hormone that is released in the stress response. In this module assignment, we will look at this hormone more closely to investigate:

  1. the molecular composition of cortisol
  2. the signaling pathway that elicits the production and release of cortisol
  3. the cellular-, organ-, and organ system-level response that results from this cell signal

Case Assignment

Read the following articles:

The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis. Randall, M. 2011. Dartmouth Undergraduate Journal of Science.

and

The Relationship between Traumatic Stress, PTSD and Cortisol. Delaney, E. Naval Center for Combat & Operational Stress Control.

After reading these articles, develop a 10–15 slide presentation in the following format.

Slides 1 and 2: The cascade of hormonal signals described by the section titled “Neurochemistry of Stress” of the Randall (2011) article. Use simple ovals or circles to depict the regions that release specific hormones in the hormone cascade that results in the release of cortisol. Label the hormones and regions and organs involved using textboxes (both options appear in the “Insert” tab of the PowerPoint program).

Slides 3 and 4: Label and diagram the kidney and adrenal gland. Include the following:

  • Adrenal gland: cortex and medulla; regions associated with hormone production and release; hormones released in each region
  • Kidney: cortex and medulla; region of water absorption and filtering; region of urine collection

Slide 5: Diagram and label the HPA axis. Include the hormones released by each component and their effect on the target organ(s).

Slide 6: Using your diagram from Slide 5, include the location of the hippocampus and the negative feedback loop that occurs when the hippocampus detects high cortisol levels. In the notes section, include a brief description of the effects associated with elevated cortisol exposure to the hippocampus.

Slide 7: Using bulleted points, list factors that exacerbate the stress response through activation of the HPA axis.

Slide 8–10: Do some additional research on PTSD. Diagram the regions of the brain believed to be involved with symptoms of PTSD. Explain the relationship between PTSD and depression and include relevant regions of the brain in your labeled regions.

Slides 11–13: In bulleted points, summarize the varied findings in the studies described in the article, “The Relationship between Traumatic Stress, PTSD and Cortisol.” Include the relationships found between cortisol levels and individuals with PTSD. In the notes include some explanations from the article for the variability in cortisol levels in these individuals. Explain the limitations of these studies mentioned by the author at the end of the article.

Slides 14 and 15: references cited, additional notes if necessary

Assignment Expectations

For this Case Assignment you will develop a PowerPoint presentation that is approximately 15 slides in length and addresses the requirements outlined above. Place the text containing the answers to the questions above in the Notes section of your slide presentation. Reference all of your answers in your Notes sections with citations, such as (Murray 2014). Your slides should contain labeled images that illustrate the text that you included in your Notes sections. Do a Google search that includes the term “image” to find diagrams of the required organs and systems (e.g., search for “adrenal gland image”). Provide the website or reference used for each labeled image. Be sure your last slide is a references slide that contains the full references cited on your slides. Many resources are provided for you. Include these in your references section. This assignment should not require much independent research.Privacy Policy | Contact

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Module 2 – SLP

Chronic Stress and Behavioral Response

Continue your investigation of the effects of stress on brain function and behavior. Read more about the hippocampus, amygdala, and prefrontal cortex in these articles:

“How to Prevent Stress from Shrinking Your Brain,” in Psychology Today

“Stress Effects on Structure and Function of Hippocampus,” by the Rockefeller University

Answer the following questions in paragraph format to write an essay about the findings reported by these articles:

Introduction Paragraph:

First, do some research on how the amygdala, hippocampus, and prefrontal cortex communicate and result in normal behavioral response. You will begin your reading on the amygdala by following this link. After reading this section, click on several other structures in the brain at the end of the page to read about the interactions between these three regions. Briefly describe this pathway and the behavior that results from the interaction of these regions using the format and requirements outlined below.

Body Paragraph 1

Summarize the effects of glucocorticoids on the hippocampus and prefrontal cortex reported in the article How to Prevent Stress from Shrinking Your Brain.

Body Paragraphs 2 and 3

What effect on hippocampal cells have stress hormones had in recent studies described by Stress Effects on Structure and Function of Hippocampus? What effect have they had on the amygdala in studies? What are the implications of these effects? HINT: What are the functions of the regions and how might they be affected by changes in their structure?

Body Paragraph 4

What is neurogenesis and where does it occur in the brain? What effect on the regeneration of hippocampal cells is reported in this article? What is the mechanism?

Conclusion Paragraph 1

Summarize the effects of cortisol on this pathway by describing how PTSD can result from perpetuated cortisol release and how this can result in depression by activating and/or reinforcing depression pathways.

Conclusion Paragraph 2

Describe the methods proposed to counteract the negative effects of chronic stress in How to Prevent Stress from Shrinking Your Brain.

SLP Assignment Expectations

For this assignment, write an essay using the outline above. You are provided with many scholarly references to complete this assignment. Include a References section that lists these and any additional sources you used (refer to the Background page). For any additional research you are required to do to complete your assignment, please use scholarly references such as a peer-reviewed journal article or a government-sponsored or university-sponsored website. As you read through your sources, take notes from your sources and then write your paper in your own words, describing what you have learned from your research. Direct quotes should be limited and must be designated by quotation marks. Paraphrased ideas must give credit to the original author, for example (Murray, 2014). Direct copying from “homework help” websites will not receive credit.Privacy Policy | Contact

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Module 2 – Outcomes

Chronic Stress and Behavioral Response

  • Module
    • Identify the release of cortisol in response to the HPA axis.
    • Examine the effects of cortisol on regions of the brain.     
    • Identify the regions of the brain and the neuronal pathways related to the neurobiology of depression, PTSD, and the stress response.
  • Case
    • Identify the molecular composition of cortisol and the signaling pathway that elicits the production and release of cortisol.
    • Investigate the cellular-, organ-, and organ system-level response to cortisol.
    • Investigate the relationship between traumatic stress, PTSD, and cortisol.
  • SLP
    • Identify sites of neurogenesis in the brain.
    • Identify effects of cortisol dysregulation on the amygdala, prefrontal cortex, and hippocampus.
  • Discussion
    • Investigate the relationship between stress and depression.

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Module 3 – Home

Stress and the Immune Response

Modular Learning Outcomes

Upon successful completion of this module, the student will be able to satisfy the following outcomes:

  • Case
    • Define the role of inflammatory mediators and the complement system in the inflammatory response.
    • Describe the effects of cortisol and the inflammatory response on the brain.
  • SLP
    • Apply the scientific method to modern research and theories on the relationship between cortisol and inflammation.
  • Discussion
    • Explain how the stress response impacts the immune system.

Module Overview

Now that you have learned about cortisol and its effect on the CNS, let’s continue to examine how other systems of the human body can be negatively affected by persistent cortisol exposure. We begin by learning about the systems that operate to protect our body from disease: the lymphatic and immune systems. After you work through this tutorial, look at the nonspecific and specific responses of your body’s immune response. As you can see, nonspecific responses are part of the body’s innate immune system, acting like patrolling guards at a gate. The specific responses are part of the body’s adaptive immune system, analogous to a special operations unit that is trained and equipped to handle a wide variety of situations. This includes the ability to remember invaders, which provides us with immunity to future attacks by that pathogen.

View this overview of the primary immune response to see this in action. Let’s look more closely at the “special ops” of the immune system: T and B cells. Both originate from stem cells in the bone marrow, where all blood cells are produced. They mature in different regions of the body: B cells mature in bone marrow and T cells mature in the thymus gland. We describe them as being naïve when they leave these organs, until they encounter an antigen and bind to accomplish immunocompetence.

Now look more closely at the structure of antibodies responsible for recognizing the antigen presented by the pathogen. When the antibody binds to the antigen, the pathogen is then targeted and can be removed and/or destroyed. This summarizes the idea of immunocompetence and the importance of the ability of T and B cells.

Now that you have some background on normal immune system function, proceed to the Background and Case assignments to look at how cortisol levels resulting from the stress response can influence the immune response.Privacy Policy | Contact

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Module 3 – Background

Stress and the Immune Response

Note: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.

Pearson Learning Solutions: Lymphatic and immune systems. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7101

Pearson Learning Solutions: Immune Response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5420

Pearson Learning Solutions: Primary immune response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8613

Pearson Learning Solutions: Naïve T and B cells. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8615

Pearson Learning Solutions: Antibodies. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8611

Pearson Learning Solutions: Antigen Binding. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8612

Pearson Learning Solutions: Inflammatory Mediators. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8631

Pearson Learning Solutions: Inflammatory Response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8622

Pearson Learning Solutions: Complement System. Pearson Higher Education, 2014. Accessed on August 14, 2014, http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8600

Hovhannisyan,L.P. et al. Alterations in the complement cascade in post-traumatic stress disorder. Allergy Asthma Clin Immunol. 2010; 6(1): 3. Accessed on August 18, 2014, at www.ncbi.nlm.nih.gov/pmc/articles/PMC2834673/

Pearson Learning Solutions: Scientific method. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10647

Pearson Learning Solutions: Scientific Method Diagram. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=5624Privacy Policy | Contact

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Module 3 – Case

Stress and the Immune Response

STOP!!! BE SURE YOU HAVE READ THE CONTENT ON THE HOME PAGE AND ALL LINKS THERE! You will need this information to continue with this assignment.

Case Assignment

Now that you know about the immune response, return to the article The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis in the Dartmouth Undergraduate Journal of Science and read the section related to the immune system in closer detail. Using this as a starting point, complete the requirements below using paragraph format to address each topic:

Paragraph 1: Introduction

Note that the inflammatory response and the complement system are mentioned in the article. Now learn more about the inflammatory response and the inflammatory mediators. You will find information on the complement system as well. Do a little research on these components and provide a paragraph explaining the normal function and steps associated with signaling these components. Identify where in this cascade of signaling events that cortisol is thought to interfere.

Paragraph 2: PTSD and the Complement System

Now compare the theory mentioned in the Dartmouth article to the findings in this study on PTSD and the complement system. Focus on the Abstract and Discussion sections of this study on PTSD. Address the following questions:

  1. What did they find in common among PTSD patients?
  2. How does alteration of the complement affect the inflammatory response?

Paragraph 3: Inflammatory

Response and the Brain

Finally, read The Consequences of the Inflamed Brain and draw connections between the inflammatory response and brain function and behavior. How are the CNS and the immune system interconnected? How does the inflammatory response affect mood and behavior?

Which component of the nervous system reacts to an infection? What are the implications for mood and behavior if the inflammatory response is prolonged? What types of things might cause the inflammatory response to become prolonged or exaggerated?

Paragraph 4: Conclusions

To complete this assignment, “connect the dots” between the influence of stress on the immune system, the potential effects that PTSD can have on the inflammatory response (remember this occurs after an extremely stressful event and is related to dysregulation of cortisol), and the perpetuation of depression and other symptoms of PTSD.

Assignment Expectations

You are provided with many scholarly references to complete this assignment. Include a References section that lists these and any additional sources you used (refer to the Background page). For any additional research you are required to do to complete your assignment, please use scholarly references such as a peer-reviewed journal article or a government-sponsored or university-sponsored website. As you read through your sources, take notes from your sources and then write your paper in your own words, describing what you have learned from your research. Direct quotes should be limited and must be designated by quotation marks. Paraphrased ideas must give credit to the original author, for example (Murray, 2014). Direct copying from “homework help” websites will not receive credit.

For this Case Assignment, answer all questions using full sentences and use the headings provided above to organize your paper.Privacy Policy | Contact

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Module 3 – SLP

Stress and the Immune Response

You must complete your Case 3 assignment before you can proceed with this assignment.

In this module’s SLP assignment, you will take a break from the anatomy and physiology of stress to analyze the work you have done so far, specifically in your Module 3 Case Assignment.

The readings you accomplished for Module 3’s Case Assignment are quite new scientific theories that are currently being tested by scientists who are trying to figure out why individuals suffer from behavioral issues such as depression and PTSD. The scientific and medical communities have collected a lot of evidence that stress plays a very big role in not only creating these behaviors, but also perpetuating them. We still have a long way to go and a lot of unanswered questions!

By completing Case 3, you have participated in the scientific method. After you view this linked animation, use this diagram as your reference point to complete the following components of this assignment:

  • In which part of the Case Assignment did you address Step 1, “observe and generalize”?
  • Which part of the Case Assignment required you to accomplish Step 2, “formulate a hypothesis”?
  • Did your hypothesis contain information that can be accepted as the absolute truth? If not, what information was missing? (HINT: Think back to the studies about cortisol and PTSD.) Based on the information that was missing from your hypothesis, what could you test in order to obtain more information on the unknown piece?
  • Do a bit of research on the technology available today that could facilitate this test. Examples of new technology include brain imaging, blood chemistry and hormone level tests, CAT scans, MRIs, and DNA mapping. What step of the scientific method does this require?
  • Now that you have some additional information, briefly and in simple terms, describe how you would test the missing information and which step of the scientific method this accomplishes.

SLP Assignment Expectations

For this SLP assignment, answer all questions using full sentences in paragraph format. For any additional research you are required to do to complete your assignment, please use scholarly references such as a peer reviewed journal article or a government sponsored or university sponsored website. As you read through your sources, take notes from your sources and then write your paper in your own words, describing what you have learned from your research. Direct quotes should be limited and must be designated by quotation marks. Paraphrased ideas must give credit to the original author, for example (Murray, 2014). Direct copying from “homework help” websites will not receive credit.Privacy Policy | Contact

content/enforced/45566-ANT100-WIN2015-1/Modules/Module3/Mod3Objectives.html/Modules/Module3/Mod3Objectives.html

Module 3 – Outcomes

Stress and the Immune Response

  • Module
    • Examine the basics of immunity and the immune response.
    • Identify the effects of chronic stress and cortisol on the inflammatory response.
    • Apply the scientific method to investigating current theories of stress-related pathologies.
  • Case
    • Define the role of inflammatory mediators and the complement system in the inflammatory response.
    • Describe the effects of cortisol and the inflammatory response on the brain.
  • SLP
    • Apply the scientific method to modern research and theories on the relationship between cortisol and inflammation.
  • Discussion
    • Explain how the stress response impacts the immune system.

Privacy Policy | Contact

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Module 4 – Home

Stress and the Cardiovascular and Digestive Systems

Modular Learning Outcomes

Upon successful completion of this module, the student will be able to satisfy the following outcomes:

  • Case
    • Identify the factors that have an effect on heart rate and blood pressure.
    • Identify the risk of stress and hypertension on the heart.
  • SLP
    • Identify the relationships between stress and weight gain.
    • Identify the effects of cortisol on blood sugar regulation.
    • Explain the relationships between obesity, blood sugar, stress, and hypertension.
  • Discussion
    • Define microbiome and explain how it contributes to digestion.
    • Explain pathways in the CNS related to digestion.

Module Overview

In this module you will examine the effects of chronic stress and cortisol dysregulation on the cardiovascular and digestive systems. First you will examine the normal structure and function of these systems, and then investigate the mechanisms behind chronic diseases associated with high stress levels, such as high blood pressure and obesity.

Let’s begin by learning more about each system. As you may already know, the cardiovascular system is a closed loop circulatory system (unlike the lymphatic system, which is an open loop), with the main function of circulating blood carrying nutrients and oxygen to the tissues of the body and removing waste products and carbon dioxide from the body’s tissues. The heart is the pump that drives this circulation. The hypothalamus in the CNS has control over heart rate and respiration. The hypothalamus sends signals directly to the heart and adrenal glands in response to signals collected from blood chemistry and pressure to adjust heart rate, keeping oxygen levels up and carbon dioxide levels down. In a crisis, the CNS and endocrine system respond to severe blood loss to return blood pressure back to normal. Complete this tutorial on the circulatory system in order to better visualize these processes.

Let’s look more closely at factors that affect blood pressure (BP). Click on this brief explanation of peripheral resistance for an illustration of its contribution to BP.

There are two mechanisms that the body uses to respond to stress that affect heart rate and BP:

  1. Signals from the sympathetic nervous system override the normal “pacemaker” of the heart to increase HR and constrict the blood vessels. Higher heart rate accompanied by vasoconstriction causes blood pressure to increase.
  2. The kidneys can also respond to a drop in BP by conserving water and returning it back to the blood stream to attempt to restore normal BP. A hormone, ACTH, is released from the adrenal medulla in response to hemorrhaging (uncontrollable bleeding) or dehydration. In summary, hormones signal water conservation to increase blood volume.

Both the CNS and endocrine systems also influence digestive system function. Complete the tutorial to learn about the anatomy and physiology of this system. Once the food that we ingest is broken down into its chemical components, the nutrients are absorbed by the small intestine. The small intestine is highly vascularized, and the nutrients enter the blood stream and the circulatory system here. As the blood vessels make their way back to the heart, they merge as the hepatic portal vein and travel to the liver. The nutrient-rich blood makes a stop at the liver, where toxins are removed and blood sugar levels are detected and corrected with the help of the hormone insulin. The contents of the blood are now appropriate to travel to the heart and enter systemic circulation. You will learn more about how insulin regulates blood sugar levels, and the effects that the stress response have on insulin, blood sugar, and fat storage.

Now review the effects of positive and negative feedback from the neuroendocrine system on both circulation and digestion before continuing on to your Case and SLP assignments.Privacy Policy | Contact

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Module 4 – Background

Stress and the Cardiovascular and Digestive Systems

Note: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.

Pearson Learning Solutions: Cardiovascular system. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8037

Pearson Learning Solutions: Factors that Affect Blood Pressure (BP). Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10472

Pearson Learning Solutions: Peripheral Resistance. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10473

Pearson Learning Solutions: Pathway of Depolarization. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10486

Pearson Learning Solutions: Pathway of Depolarization EKG. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10470

Pearson Learning Solutions: Vasoconstriction. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10445

Pearson Learning Solutions: Digestive system. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7098

Pearson Learning Solutions: Hormonal Feedback Loops. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=8198

Pearson Learning Solutions: Heart Rate. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=10491

Pearson Learning Solutions: Stress effects on the heart. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7472

American Heart Association. Stress and Blood Pressure. Accessed on August 14, 2014, at http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/Prevention TreatmentofHighBloodPressure/Stress-and-Blood-Pressure_UCM_301883_Article.jsp#mainContent

Gasperin, D. et al. Effect of psychological stress on blood pressure increase: a meta-analysis of cohort studies. Cad. Saúde Pública, Rio de Janeiro, 2009. 25(4):715-726.

Pearson Learning Solutions: Regulating blood sugar levels. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6822

Pearson Learning Solutions: Diabetes in America. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6271

Greenberg, M. Ph.D. The Mindful Self-Express Why We Gain Weight When We’re Stressed—And How Not To. Psychology Today. August 28, 2013 http://m.psychologytoday.com/blog/the-mindful-self-express/201308/why-we-gain-weight-when-we-re-stressed-and-how-not

Maglione-Garves, C.A., Kravitz, L., and Schneider, S. Cortisol Connection: Tips on Managing Stress and Weight. Accessed on August 18, 2014, at http://www.unm.edu/~lkravitz/Article%20folder/stresscortisol.html

The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis. Dartmouth Undergraduate Journal of Science. 2010. Accessed on August 18, 2014, at http://dujs.dartmouth.edu/fall-2010/the-physiology-of-stress-cortisol-and-the-hypothalamic-pituitary-adrenal-axis#.U-zmk-NdVywPrivacy Policy | Contact

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Cad. Saúde Pública, Rio de Janeiro, 25(4):715-726, abr, 2009

715

Effect of psychological stress on blood pressure increase: a meta-analysis of cohort studies

Efeito do estresse psicológico no aumento da pressão arterial: uma metanálise de estudos de coorte

1 Programa de Pós-gradu- ação em Saúde Coletiva, Universidade do Vale do Rio dos Sinos, São Leopoldo, Brasil. 2 Department of Primary Care and Social Medicine, Imperial College, London, UK. 3 Faculdade de Medicina, Universidade Federal de Pelotas, Pelotas, Brasil.

Correspondence M. P. Pattussi Programa de Pós-graduação em Saúde Coletiva, Universidade do Vale do Rio dos Sinos. Av. Unisinos 950, C. P. 275, São Leopoldo, RS 93022-000, Brasil. mppattussi@unisinos.br

Daniela Gasperin 1

Gopalakrishnan Netuveli 2

Juvenal Soares Dias-da-Costa 1,3

Marcos Pascoal Pattussi 1

Abstract

Studies have suggested that chronic exposure to stress may have an influence on increased blood pressure. A systematic review followed by a meta-analysis was conducted aiming to assess the effect of psychological stress on blood pres- sure increase. Research was mainly conducted in Ingenta, Psycinfo, PubMed, Scopus and Web of Science. Inclusion criteria were: published in any language; from January 1970 to December 2006; prospective cohort design; adults; main ex- posure psychological/emotional stress; outcome arterial hypertension or blood pressure increase ≥ 3.5mmHg. A total of 2,043 studies were found, of which 110 were cohort studies. Of these, six were eligible and yielded 23 comparison groups and 34,556 subjects. Median follow-up time and loss to follow-up were 11.5 years and 21%. Results showed individuals who had stronger responses to stressor tasks were 21% more likely to develop blood pressure increase when compared to those with less strong responses (OR: 1.21; 95%CI: 1.14- 1.28; p < 0.001). Although the magnitude of effect was relatively small, results suggest the relevance of the control of psychological stress to the non- therapeutic management of high blood pressure.

Blood Pressure; Hypertension; Psychological Stress

Introduction

According to the World Health Organization 1, non-transmissible diseases will be the leading cause of functional disability in the next two de- cades and, among chronic degenerative condi- tions, arterial hypertension will be the most im- portant cause. Hypertension is a public health concern due to its magnitude, risks, difficulty in management, high medical and social costs and severe cardiovascular and renal complications 2. The number of deaths due to hypertension as pri- mary cause was estimated to be over 7 million in 2002, approximately 13% of all reported deaths 1. Hypertensive adults will reach 1.5 billion by 2025, around 30% of the world population 3.

Hypertension management comprises drug and/or non-drug therapeutic approaches. Al- though there is clear evidence that antihyper- tensive medications are useful in controlling hy- pertension and reducing the incidence of stroke and infarction 2, long-term drug treatment can be expensive and side-effects can threaten pa- tients’ adherence to drug prescriptions 4. The identification of non-pharmacological meth- ods to prevent, or significantly delay the onset of hypertension would represent an important advance in the prevention of cardiovascular dis- ease 2. Among non-drug approaches, lifestyle changes recommended include: weight reduc- tion, a diet rich in fruits, vegetables, and low fat dairy products with a reduced content of satu-

REVISÃO REVIEW

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rated and total fat, dietary sodium reduction, en- gagement in regular aerobic physical activity and limited alcohol consumption 2. Extensive trials of over 100 randomized trials indicates the efficacy of behavioral treatments for hypertension 5. Be- havioral changes should also include anti-stress activities 6.

The Medical Subject Headings (MeSH) defi- nes stress as a pathological process resulting from body response to external forces and abnormal states that tend to affect its homeostasis. It com- prises daily events that increase physiological activities and consequently cause psychological wear and tear to some extent 7. When emotional stressors are prevailing, this condition is known as psychological stress. Modern life events such as work-related and family problems, social with- drawal, financial worries and violence are some factors that can predispose or potentate stress 8.

It has been suggested that chronic exposure to psychological stress can cause increased blood pressure and lead to hypertension development 5. A cohort study of over 3,000 young adults 9 showed that urgency/impatience behavior, and hostility assessed during young adulthood were strongly associated with a higher risk of develop- ing hypertension 15 years later. Other exposures such as depression and anxiety were also report- ed. Chronic stress due to financial strain has been reported to predict high blood pressure during three to seven years of follow-up 10. A study with 11,119 cases and 13,648 controls from 52 coun- tries 11 reported strong associations of myocardi- al infarction (cases) and more frequent periods of stress at home, more severe financial stress and more stressful life events compared with controls. In terms of myocardial infarction risk, the effect of psychosocial stress was as important in mag- nitude as traditional cardiovascular disease risk factors such as smoking, obesity, diabetes and hypertension. In addition, a systematic review of 23 treatment comparisons from 17 randomized trials conducted in patients with elevated blood pressure, demonstrated strong effects of tran- scendental meditations on reductions in blood pressure. Despite non-significant results, other anti-stress interventions such as biofeedback, progressive muscle relaxation and stress man- agement training also reported clinically impor- tant reductions in blood pressure 12. Therapies such as these may help patients to reduce the effects of stress by reducing physiologic arousal and restoring autonomic balance, thereby reduc- ing blood pressure 5.

The purpose of the present meta-analysis was to assess the effect of psychological stress on blood pressure increase.

Methods

A systematic review followed by meta-analysis of prospective cohort studies was conducted.

Search strategy

The systematic search of articles was carried out based on Undertaking Systematic Reviews of Research on Effectiveness guidelines 13 and Co- chrane Reviewers’ Handbook 14. The following databases were searched: Biological Abstracts; CAB Abstracts; Ingenta; Psycinfo; PubMed; Sco- pus; Web of Science; SIGLE; NTIS; NDLTD and reference lists of the selected articles. Table 1 shows searches in the different databases.

Inclusion and exclusion criteria

Inclusion criteria were: published between Janu- ary 1970 and December 2006, with this starting date chosen because studies investigating the ef- fect of psychological stress on the development of morbid conditions were first published in that decade 15,16; prospective cohort design, this study design being one of the most appropriate for assessing causality 17 while taking into con- sideration the major issue of temporality, i.e., ex- posure prior to disease; 18 to 64 year-old normo- tensive adults; main exposure measured through reactivity or recovery, reactivity is the difference between blood pressure during the stressor task and baseline 18 and recovery is blood pressure measured after a stressful task 19; dichotomous outcome as arterial hypertension or increase in systolic and/or diastolic blood pressure ≥ 3.5mmHg; and reporting relative risks, hazard ratios or odds ratios (OR).

Articles were excluded if they were based on hypertensive men and/or women at enrollment; reported other types of stress or if outcome was measured on a continuous scale.

Study quality

The quality of studies selected for inclusion in the meta-analysis was assessed. Assessments were based on the National Institute for Health and Clinical Excellence criteria 20 including subject selection, refusals, losses to follow-up, exposure and outcome measurement, level of exposure and adjustments for confounders. Two indepen- dent evaluators conducted quality assessments.

Data extraction

Data were independently extracted by two re- searchers. The principal information obtained

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Table 1

Searches, keywords and boolean operators, number of retrieved and selected articles according to the databases.

Date of Database Keywords Retrieved Selected

search articles articles

03/Jan/2007

04/Jan/2007

08/Jan/2007

09/Jan/2007

09/Jan/2007

10/Jan/2007

10/Jan/2007

10/Jan/2007

Biological

Abstracts, CAB

Abstracts and

Psycinfo

Ingenta

PubMed

Scopus

Web of Science

NITS

SIGLE

NDLTD

(stress OR psychological stress OR emotional stress OR life stress)

AND (blood pressure OR hypertension) AND

(cohort studies OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress) AND

(blood pressure OR hypertension) AND

(cohort studies OR prospective studies OR follow-up studies)

(stress [MeSH] OR psychological stress [mh] OR emotional stress [mh] OR life stress

[mh]) AND (hypertension [MeSH] OR blood pressure [MeSH]) AND

((cohort studies [MeSH] OR risk [MeSH] OR (odds [WORD] AND ratio*

[WORD]) OR (relative [WORD] AND risk [WORD])).

Limits: Adolescent: 13-18 years, Adult: 19-44 years, Middle Aged: 45-64 years,

Publication Date from 1970/01/01 to 2006/12/31, Journal Article, Humans.years,

Middle Aged: 45-64 years, Publication Date from 1970/01/01 to

2006/12/31, Journal Article, Humans

(stress OR psychological stress OR emotional stress OR life stress) AND

(hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress) AND

(hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress) AND

(hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress l OR life stress)

AND (hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress)

AND (hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

34

62

617

13

1,158

0

0

160

0

0

5

0

5

0

0

0

included: title, authors, journal, year of publi- cation, country, number of subjects, follow-up time, losses to follow-up, age, study population, measurement of exposure, outcome and con- founders in the multivariable model.

Most studies reported OR as the measure of effect. Data extracted from each article were neperian logarithm of OR and standard error (SE). One study reported the hazard ratio 21 and another reported the relative risk 22 and these

measures were converted into OR 23. When only confidence intervals were available, they were converted into SE 14.

Data analysis

Data analyses were performed using Stata soft- ware 9.2 (Stata Corp., College Station, USA). The variability of the selected studies was evaluated through a heterogeneity test using models with

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fixed effects when the test was statistically non- significant (p ≥ 0.05) and random effects when the test was statistically significant (p < 0.05) 14. Begg’s and Egger’s tests were used to investigate the existence of publication bias 24.

To avoid potential effects of heterogeneity and assess the individual impact of each variable studied, analyses were conducted by the follow- ing subgroups: age, gender, study losses, years of follow-up, test applied, exposure measurement and multivariable analysis. Lastly, a combination of measures of effect by study was assessed as well as the impact of exclusion of each study on the combined effect.

Results

Figure 1 shows the number of studies found and reasons for exclusion at each step of the system- atic search. Of 110 cohort studies, six were select- ed yielding 23 comparison groups. For example, Steptoe et al. 25 assessed the effect of middle and highest tercile systolic and diastolic blood pres- sure recovery on two outcomes: increased blood pressure ≥ 3.5mmHg and ≥ 5mmHg, thus pro- viding 8 comparisons (2x2x2). Table 2 illustrates the study characteristics and comparisons of the meta-analysis.

Of the cohort studies included in the meta- analysis, three were from North America and three from Europe. The sum of subjects in the comparisons yielded a total of 34,556 subjects. Mean follow-up was 11.8 years ranging between 3 to 25 years. Loss to follow-up ranged from be- tween 8.3% and 34.2%. In most studies, expo- sure was measured through reactivity to mental tasks. The main method of analysis was logistic regression and the main measure of effect was OR (Table 2).

The Q test showed the existence of heteroge- neity among studies (Figures 2 and 3). Therefore results from random effect models showed that those subjects with higher reactivity/recovery were 21% more likely to have blood pressure in- crease when compared to those with lower re- activity/recovery (OR = 1.21; 95%CI: 1.14-1.28) (Figure 2). Similar results were found when only one measure of effect by study was considered (OR = 1.28; 95%CI: 1.13-1.43) (Figure 3). The ex- clusion of the Matthews et al. 21 or Markovitz’s et al. 26 studies increased the effect of psychological stress on blood pressure by about 20% (OR = 1.51; 95%CI: 1.17-1.94).

The subgroup analysis revealed significant ef- fects (OR > 2) in studies including subjects over 46 years of age, small losses to follow-up, long-term follow-up, those with a combination of stressful

tasks and those where exposure was measured through recovery (Table 3). In addition, heteroge- neity between studies was non-significant when the outcome was hypertension, exposure was measured by recovery, combinations of tests, fe- males and studies with longer years of follow-up and lower losses.

Publication bias

Both Begg’s and Egger’s tests showed statistically significant results that were confirmed by the funnel plot asymmetry.

Discussion

The present meta-analysis assessed the effect of psychological stressful tasks on blood pressure increase in adults aged between 18 and 64 years. Individuals with high increases of blood pressure during stressful tasks (reactivity) and those with high blood pressure in the recovery period after the tasks (recovery) showed greater odds of de- veloping hypertension or increased blood pres- sure. This finding corroborates other findings of studies on the association between psychological stress and blood pressure increase 27,28,29.

It has been suggested that repeated episodes of heightened cardiovascular reactivity could contribute to hypertension development by promoting vascular remodeling 30. These patho- physiological changes, in turn, could alter the long-term regulation of blood pressure by the kidneys, resulting in a shift in the blood pres- sure set point to higher levels. Poor cardiovas- cular recovery could contribute to hypertension development through the same mechanisms that have been proposed for heightened cardio- vascular reactivity 31. Alternatively, it has been hypothesized that both heightened cardiovascu- lar reactivity and poor cardiovascular recovery could be markers for other pathophysiological processes involved in the etiology of hyperten- sion, such as dysfunction in the regulation of the heart and vasculature by the autonomic nervous system 32. More specifically, heightened cardio- vascular reactivity could reflect sympathetic hy- perresponsivity or enhanced vagal withdrawal during stress, whereas poorer cardiovascular re- covery could be due to prolonged sympathetic activation, diminished vagal tone, or attenuated or delayed vagal rebound following the termina- tion of stress 33. In addition, several studies have reported associations between psychosocial variables and vascular function 34,35, inflamma- tion 36, increased blood clotting and decreased fibrinolysis 37,38.

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Figure 1

Number of selected studies and reasons for exclusion at each step of the systematic search.

N = 2,043 retrieved articles

n = 1,783 excluded articles n = 1,777 different subject (60 *) n = 1 year of publication n = 5 animals

n = 260 articles

n = 110 articles

Reasons for exclusion

n = 150 excluded articles

n = 100 excluded articles

n = 90 quasi-experiments (7 *) n = 22 reviews (5 *) n = 22 crossectional (3 *) n = 7 case-controls (1 *) n = 2 ecological (1 *) n = 2 comments n = 2 clinical trials n = 1 book n = 1 case study n = 1 test-retest

Exposure n = 36 occupational (7 *) n = 7 pos-traumatic (2 *) n = 6 stability (2 *) n = 3 hospital internment (2 *) n = 3 risk groups n = 2 financial situation (1 *) n = 2 meditation n = 1 corporal mass n = 1 lifestyle

Outcome n = 1 coronary disease

Population n = 7 adolescents (2 *) n = 4 children (2 *) n = 2 hypertension

Measure of outcome N =25 continuous (4 *)

n = 10 articles preselected to meta-analysis

n = 5 articles * + 1 reference list

Total = 6 articles

* Duplicates in different databases.

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Table 2

Descriptive characteristics of studies and comparisons of the meta-analysis.

Author Country Baseline (n) End (n) Loss (%) Years of Age Participants

follow-up

Borghi et al. 43 Italy 89 70 21.3 15 < 45 Men/Women

Carroll et al. a 44 England 1,003 796 20.6 10 35-55 Men

Carroll et al. b 44 England 1,003 796 20.6 10 35-55 Men

Markovitz et al. a 26 USA 5,115 1,557 34.2 5 45-59 Men *

Markovitz et al. b 26 USA 5,115 1,557 34.2 5 45-59 Men *

Markovitz et al. c 26 USA 5,115 1,763 34.2 5 45-59 Women *

Markovitz et al. d 26 USA 5,115 1,763 34.2 5 45-59 Women *

Matthews et al. a 21 USA 5,115 3,553 30.5 13 18-30 Men/Women

Matthews et al. b 21 USA 5,115 4,075 20.3 13 18-30 Men/Women

Matthews et al. c 21 USA 5,115 4,100 19.8 13 18-30 Men/Women

Matthews et al. d 21 USA 5,115 3,463 32.3 13 18-30 Men/Women

Matthews et al. e 21 USA 5,115 4,108 19.7 13 18-30 Men/ women

Matthews et al. f 21 USA 5,115 4,122 19.4 13 18-30 Men/Women

Menkes et al. a 22 USA 1,130 815 19.3 25 < 45 * Men

Menkes et al. b 22 USA 1,130 346 19.3 25 ≥ 45 * Men

Steptoe et al. a 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. b 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. c 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. d 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe_et al e 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. f 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. g 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. h 25 England 228 209 8.3 3 45-59 Men/Women

(continues)

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Table 2 (continued)

Descriptive characteristics of studies and comparisons of the meta-analysis.

Exposure Severity Stress task Outcome Analysis Confounders

of exposure (mm/Hg)

Reactivity DBP High Mental arithmetic HTN Logistic regression Age, BMI, sex, cholesterol,

(DBP > 95) family history of HTN, baseline SBP/DBP

Reactivity SBP * High Raven’s matrices HTN Logistic regression Age, baseline SBP

(SBP ≥ 16

DBP ≥ 90)

Reactivity DBP * High Raven’s matrices HTN Logistic regression Age, baseline SBP

(SBP ≥ 160

DBP ≥ 90)

Reactivity SBP Moderate * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP High * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP Moderate * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP High * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP * High Cold pressor * HTN Cox Regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity SBP * High Star tracing * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity SBP * High Vídeo game * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥1 40

DBP ≥ 90)

Reactivity DBP * High Cold pressor * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity DBP * High Star tracing * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity DBP * High Vídeo game * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity SBP High Cold pressor Increase ≥ 20 SBP/DBP Cox regression Age, BMI, smoking, HTN familial history, SBP

Reactivity SBP High Cold pressor Increase ≥ 20 SBP/DBP Cox regression Age, BMI, smoking, HTN familial history, SBP

Recovery SBP * Moderate * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery SBP * High * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery DBP * Moderate * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery DBP * High * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery SBP * Moderate * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

Recovery SBP * High * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

Recovery DBP * Moderate * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

Recovery DBP * High * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

HTN: hypertension; SBP: systolic blood pressure; DBP: dyastolic blood pressure; BMI: body mass index.

Note: letters at end of authors’ name shows different comparison groups within a single study.

* Indicates the location of differences between comparison groups.

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Figure 2

Random effect model, odds ratio for increased blood pressure ≥ 3.5mmHg/hipertension of the effect of responses to stressor tasks in 23 comparison groups

from 6 prospective cohorts.

Note: letters at end of authors’ name shows different comparison groups within a single study.

Another action mechanism of stress involved in blood pressure increase could be indirect. Stress would be associated to risk factors such as obesity, smoking, alcohol abuse and physical in- activity and they would cause blood pressure in- crease. For example, a meta-analysis including 69 studies demonstrated that, despite the relatively small effects, physically active subjects had bet- ter cardiovascular recovery than inactive ones 39.

In addition, the results of subgroup analysis show that individuals with higher blood pres- sure in the recovery period were twice as likely to have blood pressure increase when compared to those whose exposure was measured through reactivity. This finding suggests that cardiovascu- lar measures of recovery can provide valuable in- formation not captured in measures of reactivity and thus help predicting longitudinal changes in blood pressure 28. A study found that individuals undergoing a stressful task had late recovery of blood pressure, which suggests recovery might be a helpful predictor of blood pressure increase 39.

More pronounced effects were seen in stud- ies with small losses and longer follow-up. In prospective studies there is greater concern with subject losses when they are associated to the study outcome or risk categories. The greater the loss, the greater the likelihood of bias 40. Besides, in chronic exposures, such as stress, individuals have to be exposed for a time period long enough to set off the causal process 17. Individuals aged between 46 and 64 years were about twice more likely to develop hypertension or blood pressure increase than young adults (Table 3).

This study has several limitations. The first is due to the heterogeneity of the studies selected. Measures of effect of highly heterogeneous stud- ies have low validity 41. In this study, heterogene- ity was mostly due to differences in study popula- tions, measures of exposure and outcome, losses and follow-up time. The effect of heterogeneity was partially overcome by the use of random ef- fects models, subgroup analysis, a combination of effect by study and analysis of the impact of

Odds ratio.1 .5 1 2 10

Combined

Menkes et al. b 22 Menkes et al. a 22

Markovitz et al. d 26 Markovitz et al. c 26 Markovitz et al. b 26 Markovitz et al. a 26

Carroll et al. b 44 Carroll et al. a 44

Matthews et al. f 21 Matthews et al. e 21 Matthews et al. d 21 Matthews et al. c 21 Matthews et al. b 21 Matthews et al. a 21

Borghi et al. 43 Steptoe et al. h 25 Steptoe et al. g 25 Steptoe et al. f 25 Steptoe et al. e 25 Steptoe et al. d 25 Steptoe et al. c 25 Steptoe et al. b 25 Steptoe et al. a 25 3.60

1.86 4.10 0.94 8.58 2.77 3.39 0.86 2.10 1.14 1.13 1.12 1.14 1.19 1.21 1.11 1.35 1.99 1.40 1.11 1.11 2.80 1.79

Study (95%CI)

1.20 0.85 1.29 0.40 2.05 0.94 1.13 0.29 1.04 1.05 1.04 1.05 1.05 1.10 1.12 0.91 0.91 1.40 1.18 0.79 1.02 1.47 0.71

10.78 4.07

13.02 2.23

35.90 8.15

10.15 2.58 4.24 1.23 1.22 1.18 1.23 1.28 1.31 1.34 2.00 2.84 1.68 1.54 1.20 5.35 4.49

1.21 1.14 1.28

OR Lower Upper

Heterogeneity Q = 54.8 p < 0.001

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Figure 3

Random effects model, odds ratio and 95% confi dence interval for the combined effect by study and the impact of the exclusion of each study.

exclusion of each study on the final combined effect 41. The second limitation is the detection of publication bias, which calls for a careful in- terpretation of findings. However, an evaluation comprising 48 systematic reviews of the Co- chrane database demonstrated that, despite the fact that biases were seen in 50% of the studies, they significantly affected results in less than 10% of meta-analyses 42. Third, although laboratory stress measurements potentially allow for great- er control on the part of the investigator, stress tasks were applied on an acute basis and stress is assumed to occur chronically thus limiting test conclusions. The fourth limitation is related to the fact that the majority of studies included in the meta-analysis reported OR as measure of ef- fect. When an outcome is commonly seen in a study population (as is the case of blood pressure increase), the OR might overestimate the effect of association 23. However, further analyses showed that when OR were converted into relative risks, a relative risk of 1.17 (95%CI: 1.10-1.25) was found for the combined effect. There seems to remain an effect of stress on blood pressure increase.

In conclusion, although the magnitude of effect was relatively small, results point to the relevance of control of psychological stress for the non-therapeutic management of high blood pressure. Further research investigating the role of stress in hypertension pathogenesis should be conducted.

Steptoe et al. 25

Borghi et al. 43

Matthews et al. 21

Carroll et al. 44

Markovitz et al. 26

Menkes et al. 22

Meta-analysis random-effects estimates (exponential form) Study ommited

1.13 1.28 1.43 1.96

Combined effect

Heterogeneity Q = 22.1 p < 0.001

1.09

Study (95%CI)

1.19

1.25

1.52

1.33

1.51

1.22

1.09

1.12

1.18

1.15

1.17

1.10

1.29

1.40

1.96

1.53

1.94

1.35

OR Lower Upper

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Table 3

Combined effect of psychological stress on the increase of the blood pressure in sub-groups of cohorts according to participants and study design.

Variables Number of Size of the OR (95%CI) * p-value Heterogeneity

combined sample

Age (years)

18-45 12 30,946 1.18 (1.12-1.24) < 0.001 p = 0.002

46-64 9 2,018 2.12 (1.51-2.97) < 0.001 p = 0.113

18-64 2 1,592 1.15 (0.97-1.37) 0.118 p = 0.371

Sex

Men 6 5,867 1.51 (1.20-1.90) < 0.001 p = 0.015

Women 2 3,526 1.11 (1.02-1.19) 0.01 p = 1.0

Men/Women 15 25,163 1.18 (1.11-1.25) < 0.001 p = 0.006

Loss (%)

0-10 9 1,742 2.16 (1.56-4.66) < 0.001 p = 0.118

11-20 7 13,891 1.17 (1.12-1.22) < 0.001 p = 0.116

21 or more 7 18,923 1.18 (1.10-1.26) < 0.001 p = 0.009

Years of follow-up

0-10 14 9,904 1.44 (1.20-1.73) < 0.001 p < 0.001

11-20 7 23,491 1.15 (1.12-1.18) < 0.001 p = 0.393

21 or more 2 1,161 2.41 (1.42-4.10) < 0.001 p = 0.433

Test

Combined 8 1,672 2.17 (1.51-3.12) < 0.001 p = 0.076

Arithmetic 3 1,662 1.19 (1.01-1.41) 0.044 p = 0.181

Videogame 6 14,862 1.21 (1.10-1.32) < 0.001 p = 0.003

Cold pressor 4 8,177 1.19 (1.04-1.36) 0.01 p = 0.041

Star tracing 2 8,183 1.16 (1.09-1.22) < 0.001 p = 0.377

Exposure

Reactivity 15 32,884 1.18 (1.12-1.24) < 0.001 p = 0.007

Recovery 8 1,672 2.17 (1.51-3.12) < 0.001 p = 0.076

Outcome

HTN 11 26,244 1.15 (1.12-1.19) < 0.001 p = 0.124

SBP/DBP increase ≥ 3.5mmHg 12 8,312 1.59 (1.25-2.03) < 0.001 p < 0.001

Multivariable analysis

Yes 19 27,916 1.19 (1.12-1.27) < 0.001 p = 0.002

No 4 6,640 1.32 (1.05-1.66) < 0.001 p = 0.002

HTN: hypertension; SBP: systolic blood pressure; DBP: dyastolic blood pressure.

* Fixed effects models are used when the heterogeneity test was statistically non-signifi cant (p ≥ 0.05) and random effects models when the test was statisti-

cally signifi cant.

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Resumo

Estudos sugerem que a exposição crônica ao estresse tenha influência no aumento dos níveis pressóricos. Foi realizada uma revisão sistemática seguida de me- tanálise com o objetivo de avaliar o efeito do estresse psicológico no aumento da pressão arterial. As princi- pais bases de dados utilizadas foram Ingenta, Psycinfo, PubMed, Scopus e Web of Science. Os critérios de inclu- são foram: publicado entre janeiro de 1970 e dezembro de 2006, delineamento de coorte prospectiva, adultos, estresse psicológico/emocional como exposição prin- cipal, hipertensão arterial ou aumento na pressão arterial ≥ 3,5mmHg como desfecho. A busca resultou em 2.043 artigos, sendo 110 coortes. Desses, seis eram elegíveis, os quais geraram 23 grupos de comparação e 34.556 sujeitos. A mediana do tempo de seguimento e do percentual de perdas foi 11,5 anos e 21%. Indiví- duos com maior reação a tarefas estressoras possuíam 21% mais chances de apresentar aumento na pressão arterial quando comparados com aqueles com menor reação (OR = 1,21; IC95%: 1,14-1,28; p < 0,001). Embo- ra com magnitude de efeito relativamente modesta, os resultados sugerem a importância do controle do es- tresse psicológico no tratamento não medicamentoso da hipertensão arterial sistêmica.

Pressão Arterial; Hipertensão; Estresse Psicológico

Contributors

D. Gasperin initiated the study, conducted the syste- matic review and wrote the manuscript. G. Netuveli as- sisted in the study design. J. S. Dias-da-Costa helped in theoretical aspects. M. P. Pattussi supervised the study and data analysis. All authors reviewed the manuscript and interpreted results.

Acknowledgments

D. Gasperin was supported by a scholarship from the Universidade do Vale do Rio dos Sinos (UNISINOS; pro- cess nº. 03/03013-4). Thanks go to Dr. Juraci A. Cesar for valuable comments on the project and manuscript.

References

1. World Health Organization. The World Health Re- port 2002: reducing risks, promoting healthy life. Geneva: World Health Organization; 2002.

2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr. JL, et al. The Seventh Report of the Joint National Committee on Prevention, De- tection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560-72.

3. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hyperten- sion: analysis of worldwide data. Lancet 2005; 365: 217-23.

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5. Linden W, Moseley JV. The efficacy of behavioral treatments for hypertension. Appl Psychophysiol Biofeedback 2006; 31:51-63.

6. Khan NA, Hemmelgarn B, Herman RJ, Rabkin SW, McAlister FA, Bell CM, et al. The 2008 Canadian Hypertension Education Program recommenda- tions for the management of hypertension: part 2 – therapy. Can J Cardiol 2008; 24:465-75.

7. McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 2007; 87:873-904.

8. Stansfeld S, Marmot, editors. Stress and the heart: psychosocial pathways to coronary heart disease. London: BMJ Books; 2002.

9. Yan LL, Liu K, Matthews KA, Daviglus ML, Fergu- son TF, Kiefe CI. Psychosocial factors and risk of hypertension: the Coronary Artery Risk Develop- ment in Young Adults (CARDIA) study. JAMA 2003; 290:2138-48.

10. Steptoe A, Brydon L, Kunz-Ebrecht S. Changes in financial strain over three years, ambulatory blood pressure, and cortisol responses to awakening. Psychosom Med 2005; 67:281-7.

11. Rosengren A, Hawken S, Ounpuu S, Sliwa K, Zubaid M, Almahmeed WA, et al. Association of psychoso- cial risk factors with risk of acute myocardial in- farction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364:953-62.

12. Maxwell VR, Schneider RH, Ndich SI, Gaylord-King C, Salerno JW, Anderson JW. Stress reduction pro- grams in patients with elevated blood pressure: a systematic review and metanalysis. Curr Hyper- tens Rep 2007; 9:520-8.

13. Centre for Reviews and Dissemination. Undertak- ing systematic reviews for research on effective- ness. New York: University of York; 2001.

14. Green S, Higgins JPT. Cochrane handbook for sys- tematic reviews of interventions 4.2.6. Chichester: John Wiley and Sons; 2006.

15. Bartrop RW, Luckhurst E, Lazarus L, Kiloh LG, Penny R. Depressed lymphocyte function after be- reavement. Lancet 1977; 1:834-6.

Gasperin D et al.726

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16. Dorian B, Garfinkel P, Brown G, Shore A, Gladman D, Keystone E. Aberrations in lymphocyte subpop- ulations and function during psychological stress. Clin Exp Immunol 1982; 50:132-8.

17. Rothman KJ, Greenland S. Cohort studies. In: Rothman KJ, Greenland S, editors. Modern epide- miology. 2nd Ed. Philadelphia: Lippincott Williams & Wilkins; 1998. p. 79-92.

18. Treiber FA, Kamarck T, Schneiderman N, Sheffield D, Kapuku G, Taylor T. Cardiovascular reactivity and development of preclinical and clinical dis- ease states. Psychosom Med 2003; 65:46-62.

19. Rutledge T, Linden W, Paul D. Cardiovascular re- covery from acute laboratory stress: reliability and concurrent validity. Psychosom Med 2000; 62:648-54.

20. National Institute for Health and Clinical Excel- lence. The guideline manual. Appendix D method- ology checklist: cohort studies. London: National Institute for Health and Clinical Excellence; 2007.

21. Matthews KA, Katholi CR, McCreath H, Whooley MA, Williams DR, Zhu S, et al. Blood pressure reac- tivity to psychological stress predicts hypertension in the CARDIA study. Circulation 2004; 110:74-8.

22. Menkes MS, Matthews KA, Krantz DS, Lundberg U, Mead LA, Qaqish B, et al. Cardiovascular reactivity to the cold pressor test as a predictor of hyperten- sion. Hypertension 1989; 14:524-30.

23. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998; 280:1690-1.

24. Sutton AJ, Duval SJ, Tweedie RL, Abrams KR, Jones DR. Empirical assessment of effect of publication bias on meta-analyses. BMJ 2000; 320:1574-7.

25. Steptoe A, Marmot M. Impaired cardiovascular re- covery following stress predicts 3-year increases in blood pressure. J Hypertens 2005; 23:529-36.

26. Markovitz JH, Raczynski JM, Wallace D, Chettur V, Chesney MA. Cardiovascular reactivity to video game predicts subsequent blood pressure increas- es in young men: the CARDIA study. Psychosom Med 1998; 60:186-91.

27. Carroll D, Ring C, Hunt K, Ford G, Macintyre S. Blood pressure reactions to stress and the predic- tion of future blood pressure: effects of sex, age, and socioeconomic position. Psychosom Med 2003; 65:1058-64.

28. Stewart JC, France CR. Cardiovascular recovery from stress predicts longitudinal changes in blood pressure. Biol Psychol 2001; 58:105-20.

29. Treiber FA, Musante L, Kapuku G, Davis C, Litaker M, Davis H. Cardiovascular (CV ) responsivity and recovery to acute stress and future CV functioning in youth with family histories of CV disease: a 4- year longitudinal study. Int J Psychophysiol 2001; 41:65-74.

30. Schwartz AR, Gerin W, Davidson KW, Pickering TG, Brosschot JF, Thayer JF, et al. Toward a causal mod- el of cardiovascular responses to stress and the de- velopment of cardiovascular disease. Psychosom Med 2003; 65:22-35.

31. Gibbons GH. Pathobiology of hypertension. In: Topol EJ, Califf RM, editors. Comprehensive car- diovascular medicine. Philadelphia: Lippincott Williams & Wilkins; 1998. p. 2907-18.

32. Manuck SB. Cardiovascular reactivity in cardiovas- cular disease: “once more unto the breach”. Int J Behav Med 1994; 1:4-31.

33. Mezzacappa ES, Kelsey RM, Katkin ES, Sloan RP. Vagal rebound and recovery from psychological stress. Psychosom Med 2001; 63:650-7.

34. Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, et al. Mental stress induces transient endothelial dysfunction in humans. Cir- culation 2000; 102:2473-8.

35. Kop WJ, Krantz DS, Howell RH, Ferguson MA, Pa- pademetriou V, Lu D, et al. Effects of mental stress on coronary epicardial vasomotion and flow ve- locity in coronary artery disease: relationship with hemodynamic stress responses. J Am Coll Cardiol 2001; 37:1359-66.

36. Lewthwaite J, Owen N, Coates A, Henderson B, Steptoe A. Circulating human heat shock protein 60 in the plasma of British civil servants: relation- ship to physiological and psychosocial stress. Cir- culation 2002; 106:196-201.

37. von Kanel R, Mills PJ, Fainman C, Dimsdale JE. Ef- fects of psychological stress and psychiatric dis- orders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 2001; 63:531-44.

38. Brunner E, Davey Smith G, Marmot M, Canner R, Beksinska M, O’Brien J. Childhood social circum- stances and psychosocial and behavioural fac- tors as determinants of plasma fibrinogen. Lancet 1996; 347:1008-13.

39. Schuler JL, O’Brien WH. Cardiovascular recovery from stress and hypertension risk factors: a meta- analytic review. Psychophysiology 1997; 34:649-59.

40. Altman DG. Designing research. In: Altman DG, editor. Practical statistics for medical research. London: Chapman & Hall; 1991. p. 74-106.

41. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557-60.

42. Sterne JA, Egger M, Smith GD. Systematic reviews in health care: Investigating and dealing with pub- lication and other biases in meta-analysis. BMJ 2001; 323:101-5.

43. Borghi C, Veronesi M, Bacchelli S, Esposti DD, Cosentino E, Ambrosioni E. Serum cholesterol levels, blood pressure response to stress and in- cidence of stable hypertension in young subjects with high normal blood pressure. J Hypertens 2004; 22:265-72.

44. Carroll D, Smith GD, Shipley MJ, Steptoe A, Brunner EJ, Marmot MG. Blood pressure reactions to acute psychological stress and future blood pressure status: a 10-year follow-up of men in the White- hall II study. Psychosom Med 2001; 63:737-43.

Submitted on 07/May/2008 Final version resubmitted on 08/Oct/2008 Approved on 14/Oct/2008

content/enforced/45566-ANT100-WIN2015-1/Modules/Module4/Mod4Case.html/Modules/Module4/Mod4Case.html

Module 4 – Case

Stress and the Cardiovascular and Digestive Systems

STOP!!! YOU MUST HAVE COMPLETED THE TUTORIALS ON THE CARDIOVASCULAR SYSTEM ON THE HOME PAGE BEFORE YOU WILL BE ABLE TO COMPLETE THIS ASSIGNMENT!

Case Assignment

In this Case Assignment, you will address the following in a 2- to 3-page essay:

First complete this exercise to identify the factors that have an effect on heart rate.

In your introductory paragraph, explain:

  1. Which factors contributed to an increase in HR, and
  2. Which factors contributed to a decrease in HR?

Now view the video Stress effects on the heart and read the following resources on hypertension and stress:

Stress and Blood Pressure, by the American Heart Association

Effect of psychological stress on blood pressure increase: a meta-analysis of cohort studies. Gasperin, D et al. 2009. Cad. Saúde Pública, Rio de Janeiro, 25(4):715-726.

Based on what you read and observed, address the following questions in the body of your essay:

  1. What is the risk of stress on the heart?
  2. What are the contributions of the nervous system to the increased workload that the heart experiences when an individual is stressed?
  3. Do some additional research to define “myocardial infarction risk.” What do Gasperin et al. (2009) say about the relationship between stress and myocardial infarction risk?
  4. Using the resources above, define “hypertension.” Summarize the results reported by Gasperin et al. (2009) about stress and hypertension. What was successful in lowering hypertension?
  5. In a conclusion paragraph write about what surprised you as you completed the readings/video for this Case study?

Assignment Expectations

You are provided with many scholarly references to complete this assignment. Include a References section that lists these sources (refer to the Background page). For any additional research you are required to do to complete your assignment, please use scholarly references such as a peer-reviewed journal article or a government-sponsored or university-sponsored website. As you read through your sources, take notes from your sources and then write your paper in your own words, describing what you have learned from your research. Direct quotes should be limited and must be designated by quotation marks. Paraphrased ideas must give credit to the original author, for example (Murray, 2014). Direct copying from “homework help” websites will not receive credit.Privacy Policy | Contact

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Module 4 – SLP

Stress and the Cardiovascular and Digestive Systems

In this SLP we will investigate the effects of stress on the digestive system, including its effect on regulating blood sugar levels. As you can see, dysregulation of blood sugar levels can cause metabolic problems and unusually high or low blood sugar levels, such as in diabetes. View the trends for diabetes in America demonstrated in the graph.

Now continue to your readings for this SLP assignment:

Why We Gain Weight When We’re Stressed—And How Not To, in Psychology Today

Cortisol Connection: Tips on Managing Stress and Weight, by Christine A. Maglione-Garves, Len Kravitz, Ph.D., and Suzanne Schneider, Ph.D.

Part I: Stress and Weight Gain

Using complete sentences in paragraph format, address the following questions:

What hormones are implicated in the weight gain response that some individuals experience when stressed? Which type of stressor elicits this response? How does this influence fat deposition? What role do dietary choices and cravings play in stress-related weight gain?

Part II: Blood Sugar Regulation

Now review the article from the Dartmouth Undergraduate Science Journal:

The Physiology of Stress: Cortisol and the Hypothalamic-Pituitary-Adrenal Axis

How is the pathway described here different from those described in the first two articles? Which type of stressors influence the relationship between cortisol and insulin? Are the health risks different?

Part III: Conclusions

In a conclusion paragraph, compare and contrast the influence of short- and long-term stress effects on blood sugar regulation and fat deposition. Are these responses related to health risks in the cardiovascular system? Explain the connections between the body’s response to stress described in these articles and other health risks such a high cholesterol and hypertension.

SLP Assignment Expectations

Organize this assignment using the subtitles that summarize each group of questions. Answer each question under the subtitle using complete sentences that relate back to the question. Be sure to include a references section at the end of your assignment that lists the websites and articles used above and any additional resources you used to research your answers. Follow the format provided in the Background page.Privacy Policy | Contact

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Module 4 – Outcomes

Stress and the Cardiovascular and Digestive Systems

  • Module
    • Identify the physiology of blood pressure regulation.
    • Identify the effect of the sympathetic division of the nervous system on BP and heart rate.
    • Relate the effects of cortisol on the cardiovascular and digestive systems to the etiology of heart disease, hypertension, and diabetes.
  • Case
    • Identify the factors that have an effect on heart rate and blood pressure.
    • Identify the risk of stress and hypertension on the heart.
  • SLP
    • Identify the relationships between stress and weight gain.
    • Identify the effects of cortisol on blood sugar regulation.
    • Explain the relationships between obesity, blood sugar, stress, and hypertension.
  • Discussion
    • Define microbiome and explain how it contributes to digestion.
    • Explain pathways in the CNS related to digestion.

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content/enforced/45566-ANT100-WIN2015-1/Modules/Module5/Mod5Home.html/Modules/Module5/Mod5Home.html

Module 5 – Home

Stress Effects on the Excretory and Reproductive Systems

Modular Learning Outcomes

Upon successful completion of this module, the student will be able to satisfy the following outcomes:

  • Case
    • Identify the hormones that regulate the reproductive system.
    • Examine the influence of corticotropic-releasing hormone on the reproductive hormones and organs.
  • SLP
    • Explain the relationship between water balance and blood pressure.
    • Identify mechanisms that regulate blood pressure and water balance.
  • Discussion
    • Identify relationships between infertility, stress hormones, and population dynamics.

Module Overview

In this final module, we investigate the effects of the stress response on the excretory and reproductive systems. We have already introduced the relationship between water balance and blood pressure. We will look more closely at how the excretory system regulates water and ion balance, and the influence of stress hormones on this component of homeostasis.

The kidneys of the excretory, or urinary, system are the organs responsible for filtering toxins out of the blood and conserving or passing water depending on the body’s hydration needs. As you work through the following tutorials, keep in mind that the functional unit of the kidney is called the nephron and is composed of a network of tubules and capillaries.

  1. Movement of fluid in the body
  2. Urinary system overview
  3. How the kidney works

Now that you are familiar with the basic organization of the urinary system, kidneys, and nephron, look more closely at the physiology of the nephron where filtration and the regulation of water and ion balance occurs:

  1. Filtration at the nephron
  2. Resorption
  3. Secretion

The chemical composition of our blood is detected by sensory cells in the juxtaglomerular apparatus. If ionic content, acidity, or blood pressure (water content in the blood) is out of balance, these cells will detect the imbalance, and send signals to endocrine cells in the kidney and adrenal glands to respond. The concentration of water in the blood is also detected by the hypothalamus. When you are dehydrated, the hypothalamus signals the pituitary gland to release the hormone, ADH, which acts on the kidney tubules signaling them to conserve water. In this condition, urinary output will be very small.

With a coordination of the neuroendocrine system, the kidneys can respond to stressors that arise from an emergency situation such as hemorrhaging, and maintain water balance and blood pressure in everyday situations as well.

The reproduction system also responds to stress and stress hormones. Begin your investigation of the effects of the stress response on reproduction with these tutorials on the female and male reproductive systems. As you proceed to your Case Assignment, consider the historical/evolutionary conditions under which population density and scarcity of resources may have affected human reproduction, and how the stress response pathways have implications for fertility in the modern day.Privacy Policy | Contact

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Module 5 – Background

Stress Effects on the Excretory and Reproductive Systems

Note: If you have trouble viewing some of the course materials, install Quicktime and the Adobe Shockwave Player, both of which can be downloaded free from the Internet.

Pearson Learning Solutions: Movement of Fluids in the Body. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11140

Pearson Learning Solutions: Urinary System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6564

Pearson Learning Solutions: Nephron. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6899

Pearson Learning Solutions: Filtration through the Renal Capsule. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6885

Pearson Learning Solutions: Filtration at the Nephron. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11103

Pearson Learning Solutions: Resorption. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11109

Pearson Learning Solutions: Secretion. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11110

Pearson Learning Solutions: Juxtaglomerular Apparatus. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=6886

Pearson Learning Solutions: Dehydration Response. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=11128

Pearson Learning Solutions: Female Reproductive System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7280

Pearson Learning Solutions: Male Reproductive System. Pearson Higher Education, 2014. Accessed on August 14, 2014, at http://www.pearsoncustom.com/mct-comprehensive/asset.php?isbn=1269879944&id=7282

Sanders, R. Stress puts double whammy on reproductive system. UC Berkeley News. 15 June 2009.

Kalantaridou, N.S., et al. Stress and the female reproductive system. Journal of Reproductive Immunology. 2004.62:61-68Privacy Policy | Contact

content/enforced/45566-ANT100-WIN2015-1/Modules/Module5/Mod5Case.html/stress and female reproduction.pdf

Journal of Reproductive Immunology 62 (2004) 61–68

Review

Stress and the female reproductive system

S.N. Kalantaridoua, A. Makrigiannakisb, E. Zoumakisc, G.P. Chrousosc,d,∗

a Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Ioannina, School of Medicine, Panepistimiou Avenue, 45500 Ioannina, Greece

b Department of Obstetrics and Gynecology, University of Crete, School of Medicine, 7110 Heraklion, Greece c Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human

Development, National Institutes of Health, Building 10, Room 9D42, Bethesda, MD 20892-1583, USA d 1st Department of Pediatrics, University of Athens, School of Medicine, Athens, Greece

Received in revised form 25 September 2003; accepted 25 September 2003

Abstract

The hypothalamic–pituitary–adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteiniz- ing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Repro- ductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal toler- ance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period. © 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Decidualization; Implantation; Luteolysis; Maternal tolerance; Ovulation; Parturition; Reproductive corticotropin-releasing hormone; Stress

∗ Corresponding author. Tel.:+1-301-496-5800; fax:+1-301-402-0884. E-mail address: chrousog@mail.nih.gov (G.P. Chrousos).

0165-0378/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jri.2003.09.004

62 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68

1. Introduction

The hypothalamic–pituitary–adrenal (HPA) axis exerts an inhibitory effect on the female reproductive system (Chrousos et al., 1998). In addition, the hypothalamic neuropeptide corticotropin-releasing hormone (CRH) and its receptors have been identified in most fe- male reproductive tissues, including the ovary, uterus, and placenta. Furthermore, CRH is secreted in peripheral inflammatory sites where it exerts strong inflammatory actions. Thus, “reproductive” CRH is a form of “tissue” CRH (CRH found in peripheral tissues), analogous to the “immune” CRH (Chrousos, 1995). “Reproductive” CRH is regulating key reproductive functions with an inflammatory component, such as ovulation, luteolysis, implantation, and parturition.

2. Interactions between the hypothalamic–pituitary–adrenal axis and the female reproductive system

The hypothalamic–pituitary–adrenal axis along with the arousal and autonomic nervous systems constitute the stress system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis, and increases its chance for survival (Chrousos and Gold, 1992).

The principal regulators of the HPA axis are CRH and arginine–vasopressin (AVP), both produced by parvicellular neurons of the paraventricular nucleus of the hypothalamus into the hypophyseal portal system (Chrousos and Gold, 1992). CRH and AVP synergistically stimulate pituitary adrenocorticotropic hormone (ACTH) secretion and, subsequently, cor- tisol secretion by the adrenal cortex.

The female reproductive system is regulated by the hypothalamic–pituitary–ovarian axis. The principal regulator of the hypothalamic–pituitary–ovarian axis is gonadotropin-releasing hormone (GnRH), produced by neurons of the preoptic and arcuate nucleus of the hypotha- lamus into the hypophyseal portal system (Ferin, 1996). GnRH stimulates pituitary follicle stimulating and luteinizing hormone secretion and, subsequently, estradiol and progesterone secretion by the ovary.

The HPA axis, when activated by stress, exerts an inhibitory effect on the female repro- ductive system (Table 1). Corticotropin-releasing hormone and CRH-induced proopiome- lanocortin peptides, such as�-endorphin, inhibit hypothalamic GnRH secretion (Chen et al., 1992). In addition, glucocorticoids suppress gonadal axis function at the hypothalamic, pi- tuitary and uterine level (Sakakura et al., 1975; Rabin et al., 1990). Indeed, glucocorticoid

Table 1 Effect of the hypothalamic–pituitary–adrenal axis on the female reproductive system

Hypothalamic–pituitary–adrenal axis Effect on the female reproductive system

CRH Inhibition of GnRH secretion �-Endorphin Inhibition of GnRH secretion Cortisol Inhibition of GnRH and LH secretion, inhibition of ovarian estrogen

and progesterone biosynthesis, inhibition of estrogen actions

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68 63

administration significantly reduces the peak luteinizing hormone response to intravenous GnRH, suggesting an inhibitory effect of glucocorticoids on the pituitary gonadotroph (Sakakura et al., 1975). Furthermore, glucocorticoids inhibit estradiol-stimulated uterine growth (Rabin et al., 1990).

These effects of the HPA axis are responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome (Chrousos et al., 1998).

On the other hand, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system (Vamvakopoulos and Chrousos, 1993), which may explain women’s mood cycles and manifestations of autoimmune/allergic and inflammatory diseases that follow estradiol fluctuations. Indeed, suicide attempts and allergic bronchial asthma attacks significantly increase when the plasma estradiol level reaches its lowest level, i.e. during the late luteal and early follicular phases of the menstrual cycle (Fourestie et al., 1986; Skobeloff et al., 1996).

3. “Reproductive” corticotropin-releasing hormone

CRH and its receptors have been identified in several female reproductive organs, in- cluding the ovaries, the endometrial glands, decidualized endometrial stroma, placental tro- phoblast, syncytiotrophoblast and decidua (Mastorakos et al., 1994, 1996; Makrigiannakis et al., 1995a; Grino et al., 1987; Clifton et al., 1998; Frim et al., 1988; Petraglia et al., 1992; Jones et al., 1989; Grammatopoulos and Chrousos, 2002). “Reproductive” CRH partici- pates in various reproductive functions with an “aseptic” inflammatory component, such as ovulation, luteolysis, implantation and parturition (Table 2).

Ovarian CRH is primarily found in the theca and stroma and also in the cytoplasm of the ovum (Mastorakos et al., 1993, 1994). Corticotropin-releasing hormone type 1 (CRHR-1)

Table 2 Reproductive corticotropin-releasing hormone, potential physiologic roles and potential pathogenic effects

Reproductive CRH Potential physiologic roles Potential pathogenic effects

Ovarian CRH Follicular maturation Premature ovarian failure (↑ secretion) Ovulation Anovulation (↓ secretion) Luteolysis Corpus luteum dysfunction (↓ secretion) Suppression of female sex steroid production

Ovarian dysfunction (↓ secretion)

Uterine CRH Decidualization Infertility (↓ secretion) Blastocyst implantation Recurrent spontaneous abortion (↓ secretion) Early maternal tolerance

Placental CRH Labor Premature labor (↑ secretion) Maternal hypercortisolism Delayed labor (↓ secretion) Fetoplacental circulation Preeclampsia and eclampsia (↑ secretion) Fetal adrenal steroidogenesis

64 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68

receptors (similar to those of the anterior pituitary) are also detected in the ovarian stroma and theca and in the cumulus oophorus of the graafian follicle. In vitro experiments have shown that CRH exerts an inhibitory effect on ovarian steroidogenesis in a dose-dependent, interleukin (IL)-1-mediated manner (Calogero et al., 1996; Ghizzoni et al., 1997). This finding suggests that ovarian CRH has anti-reproductive actions that might be related to the earlier ovarian failure observed in women exposed to high psychosocial stress (Bromberger et al., 1997). Interestingly, CRH and its receptors have also been identified in Leydig cells of the testis, where CRH exerts inhibitory actions on testosterone biosynthesis (Fabri et al., 1990).

There is no detectable CRH in oocytes of primordial follicles in human ovaries, whereas there is abundant expression of the CRH and CRHR-1 genes in mature follicles, suggesting that CRH may play auto/paracrine roles in follicular maturation (Mastorakos et al., 1993, 1994; Asakura et al., 1997). However, polycystic ovaries present diminished amounts of CRH immunoreactivity, suggesting that decreased ovarian CRH might be related to the anovulation of polycystic ovarian syndrome (Mastorakos et al., 1994). Finally, the concen- tration of CRH is higher in the premenopausal than the postmenopausal ovaries, indicating that ovarian CRH may be related to normal ovarian function during the reproductive life span (Zoumakis et al., 2001).

The human endometrium also contains CRH (Mastorakos et al., 1996; Makrigiannakis et al., 1995a). Epithelial cells are the main source of endometrial CRH, while stroma does not express it, unless it differentiates to decidua (Mastorakos et al., 1996;Makrigiannakis et al., 1995a,b;Ferrari et al., 1995). In addition, CRH receptors type 1 are present in both epithelial and stroma cells of human endometrium (Di Blasio et al., 1997) and in human myometrium (Hillhouse et al., 1993), suggesting a local effect of endometrial CRH. Estro- gens and glucocorticoids inhibit and prostaglandin E2 stimulates the promoter of human CRH gene in transfected human endometrial cells, suggesting that the endometrial CRH gene is under the control of these agents (Makrigiannakis et al., 1996). The endometrial glands are full of CRH during both the proliferative and the secretory phases of the cycle (Mastorakos et al., 1996; Makrigiannakis et al., 1995a). However, the concentration of CRH is significantly higher in the secretory phase, associating endometrial CRH with intrauter- ine phenomena of the secretory phase of the menstrual cycle, such as decidualization and implantation (Zoumakis et al., 2001).

Early in pregnancy, the implantation sites in rat endometrium contain 3.5-fold higher concentrations of CRH compared to the interimplantation regions (Makrigiannakis et al., 1995b). Furthermore, human trophoblast and decidualized endometrial cells express Fas ligand (FasL), a pro-apoptotic molecule. These findings suggest that intrauterine CRH may participate in blastocyst implantation, while FasL may assist with maternal immune tolerance to the semi-allograft embryo. A nonpeptidic CRH receptor type 1-specific an- tagonist (antalarmin) decreased the expression of FasL by human trophoblasts, suggesting that CRH regulates the pro-apoptotic potential of these cells in an auto/paracrine fash- ion (Makrigiannakis et al., 2001). Invasive trophoblasts promoted apoptosis of activated Fas-expressing human T-lymphocytes, an effect potentiated by CRH and inhibited by CRH antagonist. In support of these findings, female rats treated with the CRH antag- onist in the first 6 days of gestation had a dose-dependent decrease of endometrial im- plantation sites and markedly diminished endometrial FasL expression (Makrigiannakis

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et al., 2001). Thus, locally produced CRH promotes implantation and maintenance of early pregnancy.

The human placenta contains CRH as well. Placental CRH is produced in syncytiotro- phoblast cells, in placental decidua and fetal membranes (Riley et al., 1991; Jones et al., 1989). Placental CRH expression increases as much as 100 times during the last 6–8 weeks of pregnancy (Frim et al., 1988). The biologic activity of CRH in maternal plasma is at- tenuated by the presence of a circulating CRH binding protein (CRH-BP), produced by the liver and placenta (Challis et al., 1995; Linton et al., 1993). Nevertheless, CRH-BP concentrations decrease during the last 6 weeks of pregnancy, leading to elevations of free CRH (Challis et al., 1995; Linton et al., 1993). Thus, placental CRH is responsible for the hypercortisolism observed during the latter half of pregnancy. This hypercortisolism is followed by a transient suppression of hypothalamic CRH secretion in the postpartum period, which may explain the blues/depression and autoimmune phenomena seen during this period (Chrousos et al., 1998; Magiakou et al., 1996; Elenkov et al., 2001).

Placental CRH induces dilation of uterine and fetal placental vessels through nitric oxide synthetase activation, and stimulation of smooth muscle contractions through prostaglandin F2alpha and E2 production by fetal membranes and placental decidua (Chrousos, 1999; Grammatopoulos and Hillhouse, 1999). Placental CRH secretion is stimulated by glucocor- ticoids, inflammatory cytokines, and anoxic conditions, including the stress of preeclampsia or eclampsia (Chrousos et al., 1998; Robinson et al., 1988; Goland et al., 1995), whereas it is repressed by estrogens (Ni et al., 2002).

CRH may be the placental clock triggering the onset of parturition (McLean et al., 1995; Challis et al., 2000; Majzoub and Karalis, 1999). Of note, experimental data have shown that CRH receptor type 1 antagonism in the sheep fetus, using antalarmin, can delay the onset of parturition (Cheng-Chan et al., 1998).

4. Conclusions

The HPA axis exerts an inhibitory effect on the female reproductive system. CRH inhibits hypothalamic GnRH secretion, whereas glucocorticoids suppress pituitary LH and ovarian estrogen and progesterone secretion and render target tissues resistant to estradiol (Chrousos et al., 1998). The HPA axis is responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome (Chrousos et al., 1998).

In addition, CRH and its receptors have been identified in female reproductive organs, including the ovaries, the endometrium and the placenta. “Reproductive” CRH partici- pates in various reproductive functions with an inflammatory component (Chrousos et al., 1998). Ovarian CRH participates in the regulation of steroidogenesis, follicular maturation, ovulation and luteolysis. Endometrial CRH participates in the decidualization, blastocyst implantation, and early maternal tolerance. Placental CRH, which is secreted mostly during the latter half of pregnancy, may be responsible for the onset of labor and the physiologic hy- percortisolism seen during this period. This hypercorticolism causes a transient postpartum adrenal suppression, which may explain the blues/depression and autoimmune phenomena of the postpartum period (Magiakou et al., 1996; Elenkov et al., 2001).

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References

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Bromberger, J.T., Matthews, K.A., Kuller, L.H., Wing, R.R., Meilahn, E.N., Plantinga, P., 1997. Prospective study of the determinants of age at menopause. Am. J. Epidemiol. 145, 124–133.

Calogero, A.E., Burrello, N., Negri-Cesi, P., Papale, L., Palumbo, M.A., Cianci, A., Sanfilippo, S., D’Agata, R., 1996. Effects of corticotropin-releasing hormone on ovarian estrogen production in vitro. Endocrinology 137, 4161–4166.

Challis, J.R., Matthews, S.G., Van Meir, C., Ramirez, M.M., 1995. Current topic: the placental corticotropin-releasing hormone-adrenocorticotrophin axis. Placenta 16, 481–502.

Challis, J.R.G., Matthews, S.G., Gibb, W., Lye, S.J., 2000. Endocrine and paracrine regulation of birth at term and preterm. Endocr. Rev. 21, 514–550.

Chen, M.D., O’Byrne, K.T., Chiappini, S.E., Hotchkiss, J., Knobil, E., 1992. Hypoglycemic “stress” and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: role of the ovary. Neuroen- docrinology 56, 666–673.

Cheng-Chan, E., Falconer, J., Madsen, G., Rice, K.C., Webster, E.L., Chrousos, G.P., Smith, R., 1998. A corticotropin-releasing hormone type 1 receptor antagonist delays parturition in sheep. Endocrinology 139, 3357–3360.

Chrousos, G.P., Gold, P.W., 1992. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 1244–1252.

Chrousos, G.P., 1995. The hypothalamic–pituitary–adrenal axis and immune-mediated inflammation. N. Engl. J. Med. 332, 1351–1362.

Chrousos, G.P., Torpy, D.J., Gold, P.W., 1998. Interactions between the hypothalamic–pituitary–adrenal axis and the female reproductive system: clinical implications. Ann. Intern. Med. 129, 229–240.

Chrousos, G.P., 1999. Reproductive placental corticotropin-releasing hormone and its clinical implications. Am. J. Obstet. Gynecol. 180 (Suppl), 249–250.

Clifton, V.L., Telfer, J.F., Thompson, A.J., Cameron, I.T., Teoh, T.G., Lye, S.J., Challis, J.R., 1998. Corticotropin-releasing hormone and proopiomelanocortin-derived peptides are present in human my- ometrium. J. Clin. Endocrinol. Metab. 83, 3716–3721.

Di Blasio, A.M., Giraldi, F.P., Vigano, P., Petraglia, F., Vignali, M., Cavagnini, F., 1997. Expression of corticotropin-releasing hormone and its R1 receptor in human endometrial stromal cells. J. Clin. Endocrinol. Metab. 82, 1594–1597.

Elenkov, I.J., Wilder, R.L., Bakalov, V.K., Link, A.A., Dimitrov, M.A., Fisher, S., Crane, M., Kanik, K.S., Chrousos, G.P., 2001. Interleukin 12, tumor necrosis factor-alpha and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J. Clin. Endocrinol. Metab. 86, 4933–4938.

Fabri, A., Tinajero, J.C., Dufau, M.L., 1990. Corticotropin-releasing factor is produced by rat Leydig cells and has a major local antireproductive role in the testis. Endocrinology 127, 1541–1543.

Ferin, M., 1996. The menstrual cycle: an integrative view. In: Adashi, E.Y., Rock, J.A., Rosenwaks, Z. (Eds.), Reproductive Endocrinology, Surgery, and Technology, vol. 1. Lippincott-Raven, Philadelphia, PA, pp. 103–121.

Ferrari, A., Petraglia, F., Gurpide, E., 1995. Corticotropin-releasing factor decidualizes human endometrial stromal cells in vitro. Interaction with progestin. J. Steroid Biochem. Mol. Biol. 54, 251–255.

Fourestie, V., de Lignieres, B., Roudot-Thoraval, F., Fulli-Lemaire, I., Cremiter, D., Nahoul, K., Fournier, S., Lejonc, J.L., 1986. Suicide attempts in hypo-estrogenic phases of the menstrual cycle. Lancet 2, 1357– 1360.

Frim, D.M., Emanuel, R.L., Robinson, B.G., Smas, C.M., Adler, G.K., Majzoub, J.A., 1988. Characterization and gestational regulation of corticotropin-releasing hormone messenger RNA in human placenta. J. Clin. Invest. 82, 287–292.

Ghizzoni, L., Mastorakos, G., Vottero, A., Barreca, A., Furlini, M., Cesarone, A., Ferrari, B., Chrousos, G.P., Bernasconi, S., 1997. Corticotropin-releasing hormone (CRH) inhibits steroid biosynthesis by cultured hu-

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man granulosa-lutein cells in a CRH and interleukin-1 receptor mediated fashion. Endocrinology 138, 4806– 4811.

Goland, R.S., Conwell, I.M., Jozak, S., 1995. The effect of preeclampsia on human placental corticotropin-releasing hormone content and processing. Placenta 16, 375–382.

Grammatopoulos, D.K., Hillhouse, E.W., 1999. Role of corticotropin-releasing hormone in onset of labour. Lancet 354, 1546–1549.

Grammatopoulos, D., Chrousos, G.P., 2002. Structural and signaling diversity of corticotropin-releasing hormone (CRH) and related peptides and their receptors: potential clinical applications of CRH receptor antagonists. Trends Endocrinol. Metab. 13, 436–444.

Grino, M., Chrousos, G.P., Margioris, A.N., 1987. The corticotropin releasing hormone gene is expressed in human placenta. Biochem. Biophys. Res. Commun. 148, 1208–1214.

Hillhouse, E.W., Grammatopoulos, D., Milton, N.G., Quartero, H.W., 1993. The identification of a human myome- trial corticotropin-releasing hormone receptor that increases in affinity during pregnancy. J. Clin. Endocrinol. Metab. 76, 736–741.

Jones, S.A., Brooks, A.N., Challis, J.R., 1989. Steroids modulate corticotropin-releasing hormone production in human fetal membranes and placenta. J. Clin. Endocrinol. Metab. 68, 825–830.

Linton, E.A., Perkins, A.V., Woods, R.J., Eben, F., Wolfe, C.D., Behan, D.P., Potter, E., Vale, W.W., Lowry, P.J., 1993. Corticotropin releasing hormone-binding protein (CRH-BP): plasma levels during the third trimester of normal human pregnancy. J. Clin. Endocrinol. Metab. 76, 260–262.

Magiakou, M.A., Mastorakos, G., Rabin, D., Dubbert, B., Gold, P.W., Chrousos, G.P., 1996. Hypotha- lamic corticotropin releasing hormone suppression during the postpartum period: implications for the increase of psychiatric manifestations during this time. J. Clin. Endocrinol. Metab. 81, 1912– 1917.

Majzoub, J.A., Karalis, K.P., 1999. Placental corticotropin-releasing hormone: function and regulation. Am. J. Obstet. Gynecol. 180 (Suppl), 242–246.

Makrigiannakis, A., Zoumakis, E., Margioris, A.N., Theodoropoulos, P., Stournaras, C., Gravanis, A., 1995a. The corticotropin-releasing hormone in normal and tumoral epithelial cells of human endometrium. J. Clin. Endocrinol. Metab. 80, 185–193.

Makrigiannakis, A., Margioris, A.N., Le Goascogne, C., Zoumakis, E., Nikas, G., Stournaras, C., Psychoyos, A., Gravanis, A., 1995b. Corticotropin-releasing hormone (CRH) is expressed at the implantation sites of early pregnant rat uterus. Life Sci. 57, 1869–1875.

Makrigiannakis, A., Zoumakis, E., Margioris, A.N., Stournaras, C., Chrousos, G.P., Gravanis, A., 1996. Regulation of the promoter of the human corticotropin-releasing hormone gene in transfected human endometrial cells. Neuroendocrinology 64, 85–93.

Makrigiannakis, A., Zoumakis, E., Kalantaridou, S., Coutifaris, C., Margioris, A.N., Coukos, G., Rice, K.C., Gravanis, A., Chrousos, G.P., 2001. Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance. Nat. Immunol. 2, 1018–1024.

Mastorakos, G., Webster, E.L., Friedman, T.C., Chrousos, G.P., 1993. Immunoreactive corticotropin-releasing hormone and its binding sites in the rat ovary. J. Clin. Invest. 92, 961–968.

Mastorakos, G., Scopa, C.D., Vryonidou, A., Friedman, T.C., Kattis, D., Phenekos, C., Merino, M.J., Chrousos, G.P., 1994. Presence of immunoreactive corticotropin-releasing hormone in normal and polycystic ovaries. J. Clin. Endocrinol. Metab. 79, 934–939.

Mastorakos, G., Scopa, C.D., Kao, L.C., Vryonidou, A., Friedman, T.C., Kattis, D., Phenekos, C., Rabin, D., Chrousos, G.P., 1996. Presence of immunoreactive corticotropin releasing hormone in human endometrium. J. Clin. Endocrinol. Metab. 81, 1046–1050.

McLean, M., Bisits, A., Davies, J., Woods, R., Lowry, P., Smith, R., 1995. A placental clock controlling the length of human pregnancy. Nat. Med. 1, 460–463.

Ni, X., Nicholson, R.C., King, B.R., Chan, E.C., Read, M.A., Smith, R., 2002. Estrogen represses whereas the estrogen-antagonist ICI 182780 stimulates placental CRH gene expression. J. Clin. Endocrinol. Metab. 87, 3774–3778.

Petraglia, F., Tabanelli, S., Galassi, M.C., Garuti, G.C., Mancini, A.C., Genazzani, A.R., Gurpide, E., 1992. Human decidua and in vitro decidualized endometrial stromal cells at term contain immunoreactive corticotropin-releasing factor (CRF) and CRF-messenger ribonucleic acid. J. Clin. Endocrinol. Metab. 74, 1427–1431.

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Rabin, D.S., Johnson, E.O., Brandon, D.D., Liapi, C., Chrousos, G.P., 1990. Glucocorticoids inhibit estradiol- mediated uterine growth: possible role of the uterine estradiol receptor. Biol. Reprod. 42, 74–80.

Riley, S.C., Walton, J.C., Herlick, J.M., Challis, J.R., 1991. The localization and distribution of corticotropin-releasing hormone in the human placenta and fetal membranes throughout gestation. J. Clin. Endocrinol. Metab. 72, 1001–1007.

Robinson, B.G., Emanuel, R.L., Frim, D.M., Majzoub, J.A., 1988. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc. Natl. Acad. Sci. U.S.A. 85, 85 5244–5248.

Sakakura, N., Takebe, K., Nakagawa, S., 1975. Inhibition of luteinizing hormone secretion induced by synthetic LRH by long-term treatment with glucocorticoids in human subjects. J. Clin. Endocrinol. Metab. 40, 774–779.

Skobeloff, E.M., Spivey, W.H., Silverman, R., Eskin, B.A., Harchelroad, F., Alessi, T.V., 1996. The effect of the menstrual cycle on asthma presentations in the emergency department. Arch. Intern. Med. 156, 1837–1840.

Vamvakopoulos, N.C., Chrousos, G.P., 1993. Evidence of direct estrogenic regulation of human corticotropin-releasing gene expression. Potential implications for the sexual dimorphism of the stress re- sponse and immune/inflammatory reaction. J. Clin. Invest. 92, 1896–1902.

Zoumakis, E., Chatzaki, E., Charalampopoulos, I., Margioris, A.N., Angelakis, E., Koumantakis, E., Gravanis, A., 2001. Cycle and age-related changes in corticotropin-releasing hormone levels in human endometrium and ovaries. Gynecol. Endocrinol. 15, 98–102.

  • Stress and the female reproductive system
    • Introduction
    • Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system
    • “Reproductive” corticotropin-releasing hormone
    • Conclusions
    • References

content/enforced/45566-ANT100-WIN2015-1/Modules/Module5/Mod5Case.html/Modules/Module5/Mod5Case.html

Module 5 – Case

Stress Effects on the Excretory and Reproductive Systems

STOP!!! YOU MUST HAVE COMPLETED THE TUTORIALS AND VIEWED ALL LINKS ON THE MODULE 5 HOME PAGE IN ORDER TO COMPLETE THIS CASE ASSIGNMENT!!!!

Case Assignment

Now that you have reviewed the anatomy and physiology of reproduction, let’s continue to investigate the influence of the stress response on human reproductive function. We will begin by investigating the interactions between hormones responsible for regulating female reproductive cycles and the stress hormones.

First read some background on stress and reproduction in the article, “Stress puts double whammy on reproductive system,” By Robert Sanders, UC Berkeley News. 15 June 2009.

Next read the review by Kalantaridou, N.S., et al. Stress and the female reproductive system. Journal of Reproductive Immunology. 2004.62:61–68, and address the following questions in paragraph format:

  1. What term is used in this article to describe the regulatory axis of the reproductive system? What is the principle regulatory hormone for this axis?
  2. What effects does the HPA axis have on the female reproductive system? What two hormones are described in this article and what are the general effects of these hormones on female reproductive organs?
  3. Which female reproductive organs normally respond to CRH? What effect does this hormone have on these organs? What is the role of this hormonal signal in regulating reproduction? Use Table 2 and do a little outside research to look up any unfamiliar terms.
  4. Recall the information that you have reviewed in previous modules about unregulated cortisol and stress hormone release on the other systems of the body. What are the implications of dysregulation of CRH and glucocorticoids for human reproduction? Describe the physiological and psychological effects that these hormones can have relative to female reproduction.

Assignment Expectations

Organize this assignment by answering the questions above in four paragraphs that align with the numbering above. Answer each question using complete sentences that relate back to the question. Be sure to include a references section at the end of your assignment that lists the websites and articles used above and any additional resources you used to research your answers. Follow the format provided in the Background page.Privacy Policy | Contact

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Module 5 – SLP

Stress Effects on the Excretory and Reproductive Systems

Review the tutorials and links on your Home page to better develop the foundation you will need to complete this final SLP assignment.

Do a Google search of labeled images of the kidneys and the nephron. Develop a 10-slide PowerPoint presentation that addresses the following questions regarding the stress response and kidney function:

Slides 1–3: Provide an overview of kidney structure and function. Note where osmosis and ion secretion take place and how this contributes to water and BP regulation.

Slides 4–7: How do the kidneys regulate BP? What stress hormone(s) are involved? What situation(s) cause(s) this signaling pathway?

Slides 8 and 9: How do the kidneys respond to dehydration? Do a little research on the effect of caffeine on the kidney. Where in the physiology of the nephron does caffeine interfere with normal regulation of water balance?

Slide 10: References cited.

SLP Assignment Expectations

For this SLP assignment you will develop a PowerPoint presentation that is approximately 10 slides in length and addresses the requirements outlined above. Place the text containing the answers to the questions above in the Notes section of your slide presentation. Reference all of your answers in your Notes sections with citations, such as (Murray 2014). Your slides should contain labeled images that illustrate the text that you included in your Notes sections. Provide the website or reference used for each labeled image. Be sure your last slide is a references slide that contains the full references cited on your slides. Many resources are provided for you. Include these in your references section. This assignment should not require much independent research.Privacy Policy | Contact

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Module 5 – Outcomes

Stress Effects on the Excretory and Reproductive Systems

  • Module
    • Identify mechanisms of water balance and blood pressure regulation.
    • Examine the influence of cortisol on the reproductive system.
  • Case
    • Identify the hormones that regulate the reproductive system.
    • Examine the influence of corticotropic-releasing hormone on the reproductive hormones and organs.
  • SLP
    • Explain the relationship between water balance and blood pressure.
    • Identify mechanisms that regulate blood pressure and water balance.
  • Discussion
    • Identify relationships between infertility, stress hormones, and population dynamics.

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Module 6 – Home

Integration and Reflection

Modular Learning Outcomes

Upon successful completion of this module, the student will be able to satisfy the following outcomes:

  • Module
    • Reflect upon and integrate course concepts.
  • Discussion
    • Participate in a Discussion in which you will reflect on course concepts.

Course Overview

As your study in this course draws to a close, it is important to integrate the course content to ensure a comprehensive understanding of the concepts presented in each module. It is also important to step back and reflect on new levels of understanding, skills, and knowledge that you developed as a result of your efforts throughout this course. It is particularly important to reflect on the course outcomes (what you were intended to learn in this course).

Course Outcomes

  1. Define acute versus chronic stress and identify the differences in the response pathway for each (Module 1).
  2. Identify the anatomy and physiology of the parasympathetic versus sympathetic divisions of the nervous system (Module 1).
  3. Identify the components of the HPA axis and neuroendocrine response to stress (Module 1).
  4. Identify the release of cortisol in response to the HPA axis (Module 2).
  5. Examine the effects of cortisol and on regions of the brain (Module 2).     
  6. Identify the regions of the brain and the neuronal pathways related to the neurobiology of depression, PTSD, and the stress response (Module 2).
  7. Examine the basics of immunity and the immune response (Module 3).
  8. Identify the effects of chronic stress and cortisol on the inflammatory response (Module 3).
  9. Apply the scientific method to investigating current theories of stress-related pathologies (Module 3).
  10. Identify the physiology of blood pressure regulation (Module 4).
  11. Identify the effect of the sympathetic division of the nervous system on BP and heart rate (Module 4).
  12. Relate the effects of cortisol on the cardiovascular and digestive systems to the etiology of heart disease, hypertension, and diabetes (Module 4).
  13. Identify mechanisms of water balance and blood pressure regulation (Module 5).
  14. Examine the influence of cortisol on the reproductive system (Module 5).
  15. Reflect upon and integrate course concepts (Module 6).

Module 6 Assignment

  • Participate in a Discussion in which you will reflect on course concepts.
  • Prepare and submit a Reflective Essay.

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Module 6 – Reflective Essay

Integration and Reflection

Your Module 6 Task

Prepare a Reflective Essay in which you address each of the following items:

  1. Describe how you improved your knowledge, skills, abilities, and yourself in this session through this course.
  2. Evaluate the work you did during the session for the class and explain ways you could have performed better.
  3. Identify topics you did not understand or successfully implement and suggest how to improve the course material on those topics.
  4. Identify ways to measure the future effects of what you have learned in this course or your future progress/improvement.
  5. State whether you achieved the course outcomes (listed on the Module 6 Home page and course Syllabus page).

This Reflective Essay is a required course component (but not part of your final grade).

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content/enforced/45566-ANT100-WIN2015-1/Effect of psychological stress on blood pressure.pdf

Cad. Saúde Pública, Rio de Janeiro, 25(4):715-726, abr, 2009

715

Effect of psychological stress on blood pressure increase: a meta-analysis of cohort studies

Efeito do estresse psicológico no aumento da pressão arterial: uma metanálise de estudos de coorte

1 Programa de Pós-gradu- ação em Saúde Coletiva, Universidade do Vale do Rio dos Sinos, São Leopoldo, Brasil. 2 Department of Primary Care and Social Medicine, Imperial College, London, UK. 3 Faculdade de Medicina, Universidade Federal de Pelotas, Pelotas, Brasil.

Correspondence M. P. Pattussi Programa de Pós-graduação em Saúde Coletiva, Universidade do Vale do Rio dos Sinos. Av. Unisinos 950, C. P. 275, São Leopoldo, RS 93022-000, Brasil. mppattussi@unisinos.br

Daniela Gasperin 1

Gopalakrishnan Netuveli 2

Juvenal Soares Dias-da-Costa 1,3

Marcos Pascoal Pattussi 1

Abstract

Studies have suggested that chronic exposure to stress may have an influence on increased blood pressure. A systematic review followed by a meta-analysis was conducted aiming to assess the effect of psychological stress on blood pres- sure increase. Research was mainly conducted in Ingenta, Psycinfo, PubMed, Scopus and Web of Science. Inclusion criteria were: published in any language; from January 1970 to December 2006; prospective cohort design; adults; main ex- posure psychological/emotional stress; outcome arterial hypertension or blood pressure increase ≥ 3.5mmHg. A total of 2,043 studies were found, of which 110 were cohort studies. Of these, six were eligible and yielded 23 comparison groups and 34,556 subjects. Median follow-up time and loss to follow-up were 11.5 years and 21%. Results showed individuals who had stronger responses to stressor tasks were 21% more likely to develop blood pressure increase when compared to those with less strong responses (OR: 1.21; 95%CI: 1.14- 1.28; p < 0.001). Although the magnitude of effect was relatively small, results suggest the relevance of the control of psychological stress to the non- therapeutic management of high blood pressure.

Blood Pressure; Hypertension; Psychological Stress

Introduction

According to the World Health Organization 1, non-transmissible diseases will be the leading cause of functional disability in the next two de- cades and, among chronic degenerative condi- tions, arterial hypertension will be the most im- portant cause. Hypertension is a public health concern due to its magnitude, risks, difficulty in management, high medical and social costs and severe cardiovascular and renal complications 2. The number of deaths due to hypertension as pri- mary cause was estimated to be over 7 million in 2002, approximately 13% of all reported deaths 1. Hypertensive adults will reach 1.5 billion by 2025, around 30% of the world population 3.

Hypertension management comprises drug and/or non-drug therapeutic approaches. Al- though there is clear evidence that antihyper- tensive medications are useful in controlling hy- pertension and reducing the incidence of stroke and infarction 2, long-term drug treatment can be expensive and side-effects can threaten pa- tients’ adherence to drug prescriptions 4. The identification of non-pharmacological meth- ods to prevent, or significantly delay the onset of hypertension would represent an important advance in the prevention of cardiovascular dis- ease 2. Among non-drug approaches, lifestyle changes recommended include: weight reduc- tion, a diet rich in fruits, vegetables, and low fat dairy products with a reduced content of satu-

REVISÃO REVIEW

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rated and total fat, dietary sodium reduction, en- gagement in regular aerobic physical activity and limited alcohol consumption 2. Extensive trials of over 100 randomized trials indicates the efficacy of behavioral treatments for hypertension 5. Be- havioral changes should also include anti-stress activities 6.

The Medical Subject Headings (MeSH) defi- nes stress as a pathological process resulting from body response to external forces and abnormal states that tend to affect its homeostasis. It com- prises daily events that increase physiological activities and consequently cause psychological wear and tear to some extent 7. When emotional stressors are prevailing, this condition is known as psychological stress. Modern life events such as work-related and family problems, social with- drawal, financial worries and violence are some factors that can predispose or potentate stress 8.

It has been suggested that chronic exposure to psychological stress can cause increased blood pressure and lead to hypertension development 5. A cohort study of over 3,000 young adults 9 showed that urgency/impatience behavior, and hostility assessed during young adulthood were strongly associated with a higher risk of develop- ing hypertension 15 years later. Other exposures such as depression and anxiety were also report- ed. Chronic stress due to financial strain has been reported to predict high blood pressure during three to seven years of follow-up 10. A study with 11,119 cases and 13,648 controls from 52 coun- tries 11 reported strong associations of myocardi- al infarction (cases) and more frequent periods of stress at home, more severe financial stress and more stressful life events compared with controls. In terms of myocardial infarction risk, the effect of psychosocial stress was as important in mag- nitude as traditional cardiovascular disease risk factors such as smoking, obesity, diabetes and hypertension. In addition, a systematic review of 23 treatment comparisons from 17 randomized trials conducted in patients with elevated blood pressure, demonstrated strong effects of tran- scendental meditations on reductions in blood pressure. Despite non-significant results, other anti-stress interventions such as biofeedback, progressive muscle relaxation and stress man- agement training also reported clinically impor- tant reductions in blood pressure 12. Therapies such as these may help patients to reduce the effects of stress by reducing physiologic arousal and restoring autonomic balance, thereby reduc- ing blood pressure 5.

The purpose of the present meta-analysis was to assess the effect of psychological stress on blood pressure increase.

Methods

A systematic review followed by meta-analysis of prospective cohort studies was conducted.

Search strategy

The systematic search of articles was carried out based on Undertaking Systematic Reviews of Research on Effectiveness guidelines 13 and Co- chrane Reviewers’ Handbook 14. The following databases were searched: Biological Abstracts; CAB Abstracts; Ingenta; Psycinfo; PubMed; Sco- pus; Web of Science; SIGLE; NTIS; NDLTD and reference lists of the selected articles. Table 1 shows searches in the different databases.

Inclusion and exclusion criteria

Inclusion criteria were: published between Janu- ary 1970 and December 2006, with this starting date chosen because studies investigating the ef- fect of psychological stress on the development of morbid conditions were first published in that decade 15,16; prospective cohort design, this study design being one of the most appropriate for assessing causality 17 while taking into con- sideration the major issue of temporality, i.e., ex- posure prior to disease; 18 to 64 year-old normo- tensive adults; main exposure measured through reactivity or recovery, reactivity is the difference between blood pressure during the stressor task and baseline 18 and recovery is blood pressure measured after a stressful task 19; dichotomous outcome as arterial hypertension or increase in systolic and/or diastolic blood pressure ≥ 3.5mmHg; and reporting relative risks, hazard ratios or odds ratios (OR).

Articles were excluded if they were based on hypertensive men and/or women at enrollment; reported other types of stress or if outcome was measured on a continuous scale.

Study quality

The quality of studies selected for inclusion in the meta-analysis was assessed. Assessments were based on the National Institute for Health and Clinical Excellence criteria 20 including subject selection, refusals, losses to follow-up, exposure and outcome measurement, level of exposure and adjustments for confounders. Two indepen- dent evaluators conducted quality assessments.

Data extraction

Data were independently extracted by two re- searchers. The principal information obtained

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Table 1

Searches, keywords and boolean operators, number of retrieved and selected articles according to the databases.

Date of Database Keywords Retrieved Selected

search articles articles

03/Jan/2007

04/Jan/2007

08/Jan/2007

09/Jan/2007

09/Jan/2007

10/Jan/2007

10/Jan/2007

10/Jan/2007

Biological

Abstracts, CAB

Abstracts and

Psycinfo

Ingenta

PubMed

Scopus

Web of Science

NITS

SIGLE

NDLTD

(stress OR psychological stress OR emotional stress OR life stress)

AND (blood pressure OR hypertension) AND

(cohort studies OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress) AND

(blood pressure OR hypertension) AND

(cohort studies OR prospective studies OR follow-up studies)

(stress [MeSH] OR psychological stress [mh] OR emotional stress [mh] OR life stress

[mh]) AND (hypertension [MeSH] OR blood pressure [MeSH]) AND

((cohort studies [MeSH] OR risk [MeSH] OR (odds [WORD] AND ratio*

[WORD]) OR (relative [WORD] AND risk [WORD])).

Limits: Adolescent: 13-18 years, Adult: 19-44 years, Middle Aged: 45-64 years,

Publication Date from 1970/01/01 to 2006/12/31, Journal Article, Humans.years,

Middle Aged: 45-64 years, Publication Date from 1970/01/01 to

2006/12/31, Journal Article, Humans

(stress OR psychological stress OR emotional stress OR life stress) AND

(hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress) AND

(hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress) AND

(hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress l OR life stress)

AND (hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

(stress OR psychological stress OR emotional stress OR life stress)

AND (hypertension OR blood pressure) AND (cohort studies

OR prospective studies OR follow-up studies)

34

62

617

13

1,158

0

0

160

0

0

5

0

5

0

0

0

included: title, authors, journal, year of publi- cation, country, number of subjects, follow-up time, losses to follow-up, age, study population, measurement of exposure, outcome and con- founders in the multivariable model.

Most studies reported OR as the measure of effect. Data extracted from each article were neperian logarithm of OR and standard error (SE). One study reported the hazard ratio 21 and another reported the relative risk 22 and these

measures were converted into OR 23. When only confidence intervals were available, they were converted into SE 14.

Data analysis

Data analyses were performed using Stata soft- ware 9.2 (Stata Corp., College Station, USA). The variability of the selected studies was evaluated through a heterogeneity test using models with

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fixed effects when the test was statistically non- significant (p ≥ 0.05) and random effects when the test was statistically significant (p < 0.05) 14. Begg’s and Egger’s tests were used to investigate the existence of publication bias 24.

To avoid potential effects of heterogeneity and assess the individual impact of each variable studied, analyses were conducted by the follow- ing subgroups: age, gender, study losses, years of follow-up, test applied, exposure measurement and multivariable analysis. Lastly, a combination of measures of effect by study was assessed as well as the impact of exclusion of each study on the combined effect.

Results

Figure 1 shows the number of studies found and reasons for exclusion at each step of the system- atic search. Of 110 cohort studies, six were select- ed yielding 23 comparison groups. For example, Steptoe et al. 25 assessed the effect of middle and highest tercile systolic and diastolic blood pres- sure recovery on two outcomes: increased blood pressure ≥ 3.5mmHg and ≥ 5mmHg, thus pro- viding 8 comparisons (2x2x2). Table 2 illustrates the study characteristics and comparisons of the meta-analysis.

Of the cohort studies included in the meta- analysis, three were from North America and three from Europe. The sum of subjects in the comparisons yielded a total of 34,556 subjects. Mean follow-up was 11.8 years ranging between 3 to 25 years. Loss to follow-up ranged from be- tween 8.3% and 34.2%. In most studies, expo- sure was measured through reactivity to mental tasks. The main method of analysis was logistic regression and the main measure of effect was OR (Table 2).

The Q test showed the existence of heteroge- neity among studies (Figures 2 and 3). Therefore results from random effect models showed that those subjects with higher reactivity/recovery were 21% more likely to have blood pressure in- crease when compared to those with lower re- activity/recovery (OR = 1.21; 95%CI: 1.14-1.28) (Figure 2). Similar results were found when only one measure of effect by study was considered (OR = 1.28; 95%CI: 1.13-1.43) (Figure 3). The ex- clusion of the Matthews et al. 21 or Markovitz’s et al. 26 studies increased the effect of psychological stress on blood pressure by about 20% (OR = 1.51; 95%CI: 1.17-1.94).

The subgroup analysis revealed significant ef- fects (OR > 2) in studies including subjects over 46 years of age, small losses to follow-up, long-term follow-up, those with a combination of stressful

tasks and those where exposure was measured through recovery (Table 3). In addition, heteroge- neity between studies was non-significant when the outcome was hypertension, exposure was measured by recovery, combinations of tests, fe- males and studies with longer years of follow-up and lower losses.

Publication bias

Both Begg’s and Egger’s tests showed statistically significant results that were confirmed by the funnel plot asymmetry.

Discussion

The present meta-analysis assessed the effect of psychological stressful tasks on blood pressure increase in adults aged between 18 and 64 years. Individuals with high increases of blood pressure during stressful tasks (reactivity) and those with high blood pressure in the recovery period after the tasks (recovery) showed greater odds of de- veloping hypertension or increased blood pres- sure. This finding corroborates other findings of studies on the association between psychological stress and blood pressure increase 27,28,29.

It has been suggested that repeated episodes of heightened cardiovascular reactivity could contribute to hypertension development by promoting vascular remodeling 30. These patho- physiological changes, in turn, could alter the long-term regulation of blood pressure by the kidneys, resulting in a shift in the blood pres- sure set point to higher levels. Poor cardiovas- cular recovery could contribute to hypertension development through the same mechanisms that have been proposed for heightened cardio- vascular reactivity 31. Alternatively, it has been hypothesized that both heightened cardiovascu- lar reactivity and poor cardiovascular recovery could be markers for other pathophysiological processes involved in the etiology of hyperten- sion, such as dysfunction in the regulation of the heart and vasculature by the autonomic nervous system 32. More specifically, heightened cardio- vascular reactivity could reflect sympathetic hy- perresponsivity or enhanced vagal withdrawal during stress, whereas poorer cardiovascular re- covery could be due to prolonged sympathetic activation, diminished vagal tone, or attenuated or delayed vagal rebound following the termina- tion of stress 33. In addition, several studies have reported associations between psychosocial variables and vascular function 34,35, inflamma- tion 36, increased blood clotting and decreased fibrinolysis 37,38.

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Figure 1

Number of selected studies and reasons for exclusion at each step of the systematic search.

N = 2,043 retrieved articles

n = 1,783 excluded articles n = 1,777 different subject (60 *) n = 1 year of publication n = 5 animals

n = 260 articles

n = 110 articles

Reasons for exclusion

n = 150 excluded articles

n = 100 excluded articles

n = 90 quasi-experiments (7 *) n = 22 reviews (5 *) n = 22 crossectional (3 *) n = 7 case-controls (1 *) n = 2 ecological (1 *) n = 2 comments n = 2 clinical trials n = 1 book n = 1 case study n = 1 test-retest

Exposure n = 36 occupational (7 *) n = 7 pos-traumatic (2 *) n = 6 stability (2 *) n = 3 hospital internment (2 *) n = 3 risk groups n = 2 financial situation (1 *) n = 2 meditation n = 1 corporal mass n = 1 lifestyle

Outcome n = 1 coronary disease

Population n = 7 adolescents (2 *) n = 4 children (2 *) n = 2 hypertension

Measure of outcome N =25 continuous (4 *)

n = 10 articles preselected to meta-analysis

n = 5 articles * + 1 reference list

Total = 6 articles

* Duplicates in different databases.

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Table 2

Descriptive characteristics of studies and comparisons of the meta-analysis.

Author Country Baseline (n) End (n) Loss (%) Years of Age Participants

follow-up

Borghi et al. 43 Italy 89 70 21.3 15 < 45 Men/Women

Carroll et al. a 44 England 1,003 796 20.6 10 35-55 Men

Carroll et al. b 44 England 1,003 796 20.6 10 35-55 Men

Markovitz et al. a 26 USA 5,115 1,557 34.2 5 45-59 Men *

Markovitz et al. b 26 USA 5,115 1,557 34.2 5 45-59 Men *

Markovitz et al. c 26 USA 5,115 1,763 34.2 5 45-59 Women *

Markovitz et al. d 26 USA 5,115 1,763 34.2 5 45-59 Women *

Matthews et al. a 21 USA 5,115 3,553 30.5 13 18-30 Men/Women

Matthews et al. b 21 USA 5,115 4,075 20.3 13 18-30 Men/Women

Matthews et al. c 21 USA 5,115 4,100 19.8 13 18-30 Men/Women

Matthews et al. d 21 USA 5,115 3,463 32.3 13 18-30 Men/Women

Matthews et al. e 21 USA 5,115 4,108 19.7 13 18-30 Men/ women

Matthews et al. f 21 USA 5,115 4,122 19.4 13 18-30 Men/Women

Menkes et al. a 22 USA 1,130 815 19.3 25 < 45 * Men

Menkes et al. b 22 USA 1,130 346 19.3 25 ≥ 45 * Men

Steptoe et al. a 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. b 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. c 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. d 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe_et al e 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. f 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. g 25 England 228 209 8.3 3 45-59 Men/Women

Steptoe et al. h 25 England 228 209 8.3 3 45-59 Men/Women

(continues)

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Table 2 (continued)

Descriptive characteristics of studies and comparisons of the meta-analysis.

Exposure Severity Stress task Outcome Analysis Confounders

of exposure (mm/Hg)

Reactivity DBP High Mental arithmetic HTN Logistic regression Age, BMI, sex, cholesterol,

(DBP > 95) family history of HTN, baseline SBP/DBP

Reactivity SBP * High Raven’s matrices HTN Logistic regression Age, baseline SBP

(SBP ≥ 16

DBP ≥ 90)

Reactivity DBP * High Raven’s matrices HTN Logistic regression Age, baseline SBP

(SBP ≥ 160

DBP ≥ 90)

Reactivity SBP Moderate * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP High * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP Moderate * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP High * Video game Increase ≥ 8 Logistic regression –

Reactivity SBP * High Cold pressor * HTN Cox Regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity SBP * High Star tracing * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity SBP * High Vídeo game * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥1 40

DBP ≥ 90)

Reactivity DBP * High Cold pressor * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity DBP * High Star tracing * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity DBP * High Vídeo game * HTN Cox regression Age, BMI, education, SBP/DBP

(SBP ≥ 140

DBP ≥ 90)

Reactivity SBP High Cold pressor Increase ≥ 20 SBP/DBP Cox regression Age, BMI, smoking, HTN familial history, SBP

Reactivity SBP High Cold pressor Increase ≥ 20 SBP/DBP Cox regression Age, BMI, smoking, HTN familial history, SBP

Recovery SBP * Moderate * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery SBP * High * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery DBP * Moderate * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery DBP * High * Colour-word/ Increase ≥ 5 SBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline SBP

Recovery SBP * Moderate * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

Recovery SBP * High * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

Recovery DBP * Moderate * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

Recovery DBP * High * Colour-word/ Increase ≥ 3.5 DBP * Logistic regression Age, sex, job, antihypertensive medications,

Mirror tracing BMI, smoking, baseline DBP

HTN: hypertension; SBP: systolic blood pressure; DBP: dyastolic blood pressure; BMI: body mass index.

Note: letters at end of authors’ name shows different comparison groups within a single study.

* Indicates the location of differences between comparison groups.

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Figure 2

Random effect model, odds ratio for increased blood pressure ≥ 3.5mmHg/hipertension of the effect of responses to stressor tasks in 23 comparison groups

from 6 prospective cohorts.

Note: letters at end of authors’ name shows different comparison groups within a single study.

Another action mechanism of stress involved in blood pressure increase could be indirect. Stress would be associated to risk factors such as obesity, smoking, alcohol abuse and physical in- activity and they would cause blood pressure in- crease. For example, a meta-analysis including 69 studies demonstrated that, despite the relatively small effects, physically active subjects had bet- ter cardiovascular recovery than inactive ones 39.

In addition, the results of subgroup analysis show that individuals with higher blood pres- sure in the recovery period were twice as likely to have blood pressure increase when compared to those whose exposure was measured through reactivity. This finding suggests that cardiovascu- lar measures of recovery can provide valuable in- formation not captured in measures of reactivity and thus help predicting longitudinal changes in blood pressure 28. A study found that individuals undergoing a stressful task had late recovery of blood pressure, which suggests recovery might be a helpful predictor of blood pressure increase 39.

More pronounced effects were seen in stud- ies with small losses and longer follow-up. In prospective studies there is greater concern with subject losses when they are associated to the study outcome or risk categories. The greater the loss, the greater the likelihood of bias 40. Besides, in chronic exposures, such as stress, individuals have to be exposed for a time period long enough to set off the causal process 17. Individuals aged between 46 and 64 years were about twice more likely to develop hypertension or blood pressure increase than young adults (Table 3).

This study has several limitations. The first is due to the heterogeneity of the studies selected. Measures of effect of highly heterogeneous stud- ies have low validity 41. In this study, heterogene- ity was mostly due to differences in study popula- tions, measures of exposure and outcome, losses and follow-up time. The effect of heterogeneity was partially overcome by the use of random ef- fects models, subgroup analysis, a combination of effect by study and analysis of the impact of

Odds ratio.1 .5 1 2 10

Combined

Menkes et al. b 22 Menkes et al. a 22

Markovitz et al. d 26 Markovitz et al. c 26 Markovitz et al. b 26 Markovitz et al. a 26

Carroll et al. b 44 Carroll et al. a 44

Matthews et al. f 21 Matthews et al. e 21 Matthews et al. d 21 Matthews et al. c 21 Matthews et al. b 21 Matthews et al. a 21

Borghi et al. 43 Steptoe et al. h 25 Steptoe et al. g 25 Steptoe et al. f 25 Steptoe et al. e 25 Steptoe et al. d 25 Steptoe et al. c 25 Steptoe et al. b 25 Steptoe et al. a 25 3.60

1.86 4.10 0.94 8.58 2.77 3.39 0.86 2.10 1.14 1.13 1.12 1.14 1.19 1.21 1.11 1.35 1.99 1.40 1.11 1.11 2.80 1.79

Study (95%CI)

1.20 0.85 1.29 0.40 2.05 0.94 1.13 0.29 1.04 1.05 1.04 1.05 1.05 1.10 1.12 0.91 0.91 1.40 1.18 0.79 1.02 1.47 0.71

10.78 4.07

13.02 2.23

35.90 8.15

10.15 2.58 4.24 1.23 1.22 1.18 1.23 1.28 1.31 1.34 2.00 2.84 1.68 1.54 1.20 5.35 4.49

1.21 1.14 1.28

OR Lower Upper

Heterogeneity Q = 54.8 p < 0.001

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Figure 3

Random effects model, odds ratio and 95% confi dence interval for the combined effect by study and the impact of the exclusion of each study.

exclusion of each study on the final combined effect 41. The second limitation is the detection of publication bias, which calls for a careful in- terpretation of findings. However, an evaluation comprising 48 systematic reviews of the Co- chrane database demonstrated that, despite the fact that biases were seen in 50% of the studies, they significantly affected results in less than 10% of meta-analyses 42. Third, although laboratory stress measurements potentially allow for great- er control on the part of the investigator, stress tasks were applied on an acute basis and stress is assumed to occur chronically thus limiting test conclusions. The fourth limitation is related to the fact that the majority of studies included in the meta-analysis reported OR as measure of ef- fect. When an outcome is commonly seen in a study population (as is the case of blood pressure increase), the OR might overestimate the effect of association 23. However, further analyses showed that when OR were converted into relative risks, a relative risk of 1.17 (95%CI: 1.10-1.25) was found for the combined effect. There seems to remain an effect of stress on blood pressure increase.

In conclusion, although the magnitude of effect was relatively small, results point to the relevance of control of psychological stress for the non-therapeutic management of high blood pressure. Further research investigating the role of stress in hypertension pathogenesis should be conducted.

Steptoe et al. 25

Borghi et al. 43

Matthews et al. 21

Carroll et al. 44

Markovitz et al. 26

Menkes et al. 22

Meta-analysis random-effects estimates (exponential form) Study ommited

1.13 1.28 1.43 1.96

Combined effect

Heterogeneity Q = 22.1 p < 0.001

1.09

Study (95%CI)

1.19

1.25

1.52

1.33

1.51

1.22

1.09

1.12

1.18

1.15

1.17

1.10

1.29

1.40

1.96

1.53

1.94

1.35

OR Lower Upper

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Table 3

Combined effect of psychological stress on the increase of the blood pressure in sub-groups of cohorts according to participants and study design.

Variables Number of Size of the OR (95%CI) * p-value Heterogeneity

combined sample

Age (years)

18-45 12 30,946 1.18 (1.12-1.24) < 0.001 p = 0.002

46-64 9 2,018 2.12 (1.51-2.97) < 0.001 p = 0.113

18-64 2 1,592 1.15 (0.97-1.37) 0.118 p = 0.371

Sex

Men 6 5,867 1.51 (1.20-1.90) < 0.001 p = 0.015

Women 2 3,526 1.11 (1.02-1.19) 0.01 p = 1.0

Men/Women 15 25,163 1.18 (1.11-1.25) < 0.001 p = 0.006

Loss (%)

0-10 9 1,742 2.16 (1.56-4.66) < 0.001 p = 0.118

11-20 7 13,891 1.17 (1.12-1.22) < 0.001 p = 0.116

21 or more 7 18,923 1.18 (1.10-1.26) < 0.001 p = 0.009

Years of follow-up

0-10 14 9,904 1.44 (1.20-1.73) < 0.001 p < 0.001

11-20 7 23,491 1.15 (1.12-1.18) < 0.001 p = 0.393

21 or more 2 1,161 2.41 (1.42-4.10) < 0.001 p = 0.433

Test

Combined 8 1,672 2.17 (1.51-3.12) < 0.001 p = 0.076

Arithmetic 3 1,662 1.19 (1.01-1.41) 0.044 p = 0.181

Videogame 6 14,862 1.21 (1.10-1.32) < 0.001 p = 0.003

Cold pressor 4 8,177 1.19 (1.04-1.36) 0.01 p = 0.041

Star tracing 2 8,183 1.16 (1.09-1.22) < 0.001 p = 0.377

Exposure

Reactivity 15 32,884 1.18 (1.12-1.24) < 0.001 p = 0.007

Recovery 8 1,672 2.17 (1.51-3.12) < 0.001 p = 0.076

Outcome

HTN 11 26,244 1.15 (1.12-1.19) < 0.001 p = 0.124

SBP/DBP increase ≥ 3.5mmHg 12 8,312 1.59 (1.25-2.03) < 0.001 p < 0.001

Multivariable analysis

Yes 19 27,916 1.19 (1.12-1.27) < 0.001 p = 0.002

No 4 6,640 1.32 (1.05-1.66) < 0.001 p = 0.002

HTN: hypertension; SBP: systolic blood pressure; DBP: dyastolic blood pressure.

* Fixed effects models are used when the heterogeneity test was statistically non-signifi cant (p ≥ 0.05) and random effects models when the test was statisti-

cally signifi cant.

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Resumo

Estudos sugerem que a exposição crônica ao estresse tenha influência no aumento dos níveis pressóricos. Foi realizada uma revisão sistemática seguida de me- tanálise com o objetivo de avaliar o efeito do estresse psicológico no aumento da pressão arterial. As princi- pais bases de dados utilizadas foram Ingenta, Psycinfo, PubMed, Scopus e Web of Science. Os critérios de inclu- são foram: publicado entre janeiro de 1970 e dezembro de 2006, delineamento de coorte prospectiva, adultos, estresse psicológico/emocional como exposição prin- cipal, hipertensão arterial ou aumento na pressão arterial ≥ 3,5mmHg como desfecho. A busca resultou em 2.043 artigos, sendo 110 coortes. Desses, seis eram elegíveis, os quais geraram 23 grupos de comparação e 34.556 sujeitos. A mediana do tempo de seguimento e do percentual de perdas foi 11,5 anos e 21%. Indiví- duos com maior reação a tarefas estressoras possuíam 21% mais chances de apresentar aumento na pressão arterial quando comparados com aqueles com menor reação (OR = 1,21; IC95%: 1,14-1,28; p < 0,001). Embo- ra com magnitude de efeito relativamente modesta, os resultados sugerem a importância do controle do es- tresse psicológico no tratamento não medicamentoso da hipertensão arterial sistêmica.

Pressão Arterial; Hipertensão; Estresse Psicológico

Contributors

D. Gasperin initiated the study, conducted the syste- matic review and wrote the manuscript. G. Netuveli as- sisted in the study design. J. S. Dias-da-Costa helped in theoretical aspects. M. P. Pattussi supervised the study and data analysis. All authors reviewed the manuscript and interpreted results.

Acknowledgments

D. Gasperin was supported by a scholarship from the Universidade do Vale do Rio dos Sinos (UNISINOS; pro- cess nº. 03/03013-4). Thanks go to Dr. Juraci A. Cesar for valuable comments on the project and manuscript.

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34. Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, et al. Mental stress induces transient endothelial dysfunction in humans. Cir- culation 2000; 102:2473-8.

35. Kop WJ, Krantz DS, Howell RH, Ferguson MA, Pa- pademetriou V, Lu D, et al. Effects of mental stress on coronary epicardial vasomotion and flow ve- locity in coronary artery disease: relationship with hemodynamic stress responses. J Am Coll Cardiol 2001; 37:1359-66.

36. Lewthwaite J, Owen N, Coates A, Henderson B, Steptoe A. Circulating human heat shock protein 60 in the plasma of British civil servants: relation- ship to physiological and psychosocial stress. Cir- culation 2002; 106:196-201.

37. von Kanel R, Mills PJ, Fainman C, Dimsdale JE. Ef- fects of psychological stress and psychiatric dis- orders on blood coagulation and fibrinolysis: a biobehavioral pathway to coronary artery disease? Psychosom Med 2001; 63:531-44.

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39. Schuler JL, O’Brien WH. Cardiovascular recovery from stress and hypertension risk factors: a meta- analytic review. Psychophysiology 1997; 34:649-59.

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41. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327:557-60.

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43. Borghi C, Veronesi M, Bacchelli S, Esposti DD, Cosentino E, Ambrosioni E. Serum cholesterol levels, blood pressure response to stress and in- cidence of stable hypertension in young subjects with high normal blood pressure. J Hypertens 2004; 22:265-72.

44. Carroll D, Smith GD, Shipley MJ, Steptoe A, Brunner EJ, Marmot MG. Blood pressure reactions to acute psychological stress and future blood pressure status: a 10-year follow-up of men in the White- hall II study. Psychosom Med 2001; 63:737-43.

Submitted on 07/May/2008 Final version resubmitted on 08/Oct/2008 Approved on 14/Oct/2008

content/enforced/45566-ANT100-WIN2015-1/Gut-brain axis.pdf

Gut–brain axis: how the microbiome influences anxiety and depression Jane A. Foster and Karen-Anne McVey Neufeld

Department of Psychiatry and Behavioural Neurosciences, McMaster University, at St. Joseph’s Healthcare, 50 Charlton Ave. E,

T3308, Hamilton, ON, L8N 4A6, Canada

Review

Glossary

Bacterial colonization: naturally occurring bacterial colonization of infants

(human) or pups (rodents) begins at birth and continues through postnatal life.

Experimentally, mice lacking microbiota (GF mice) can be colonized by

removal from the gnotobiotic rearing conditions, followed by exposure to

microbiota (often exposure to mouse feces); these mice are referred to as

‘conventionalized’ mice.

Bacterial phyla: several bacteria phyla are represented in the intestinal

microbiome, including Firmicutes, Bacteroides, Proteobacteria, Actinobacteria,

Fusobacteria, and Verrucomicrobia. Recent metagenomic population studies

have attempted to classify different profiles of bacterial phyla across groups of

humans that are referred to as ‘enterotypes’.

Commensal intestinal microbiota: the human intestine is home to nearly 100

trillion microbes. The relation between these microbes and their host begins at

birth and continues throughout life as a mutually beneficial relation. These

naturally occurring, ever-present microbes are referred to as commensal

intestinal microbiota or commensals.

Microbiome: refers to the collection of microbes and their genetic material in a

particular site, for example the human GI tract.

Probiotics: live microorganisms that are administered as dietary supplements

Within the first few days of life, humans are colonized by commensal intestinal microbiota. Here, we review re- cent findings showing that microbiota are important in normal healthy brain function. We also discuss the rela- tion between stress and microbiota, and how alterations in microbiota influence stress-related behaviors. New studies show that bacteria, including commensal, probi- otic, and pathogenic bacteria, in the gastrointestinal (GI) tract can activate neural pathways and central nervous system (CNS) signaling systems. Ongoing and future animal and clinical studies aimed at understanding the microbiota–gut–brain axis may provide novel approaches for prevention and treatment of mental ill- ness, including anxiety and depression.

Introduction The human intestine harbors nearly 100 trillion bacteria that are essential for health [1]. These organisms make critical contributions to metabolism by helping to break down complex polysaccharides that are ingested as part of the diet and they are critical to the normal development of the immune system. Recent studies reveal the impor- tance of gut microbiota to the function of the CNS [2–6]. Bidirectional communication between the brain and the gut has long been recognized. Established pathways of communication include the autonomic nervous system (ANS), the enteric nervous system (ENS), the neuroen- docrine system, and the immune system. Recently, there has been a rethinking of how the CNS and periphery communicate, largely due to a growing body of experi- mental data from animal studies focused on the micro- biome (see Glossary). Neuroscientists are now taking notice of these novel reports that highlight the ‘bottom- up’ influence of microbes themselves, with several stud- ies showing that commensal bacteria are important to CNS function.

In this review, we discuss current experimental data on how gut microbiota influence the brain. Based on recent discoveries, we suggest that gut microbiota are an impor- tant player in how the body influences the brain, contribute to normal healthy homeostasis, and influence risk of dis- ease, including anxiety and mood disorders (Figure 1). Although much of this work is preclinical, we also review the limited work in the clinical arena to date.

Corresponding author: Foster, J.A. (jfoster@mcmaster.ca). Keywords: microbiota; behavior; anxiety; gut–brain axis; germ-free; stress.

0166-2236/$ – see front matter � 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.101

Overview of the microbiome Early postnatal life in mammals represents a period of bacterial colonization. Resident or commensal microbiota colonize the mammalian gut shortly after birth and remain there throughout life. In humans, the lower intestine con- tains 1014–1015 bacteria, that is, there are 10–100 times more bacteria in the gut than eukaryotic cells in the human body (1013) [1,7,8]. The presence of commensal microbiota is critical to immune function, nutrient processing, and other aspects of host physiology [9–13]. As we discuss here, microbiota are also important in the function of the CNS.

To understand effectively the role of commensal micro- biota in health and disease, we must be able to describe the complex ecology of the microbiome. Recently developed molecular and metagenomic tools have allowed research- ers to better understand the structure and function of the microbial gut community. Several bacterial phyla are represented in the gut, and commensals exhibit consider- able diversity, with as many as 1000 distinct bacterial species involved [14–16]. The two most prominent phyla are Firmicutes and Bacteroides, accounting for at least 70– 75% of the microbiome [15–17]. Proteobacteria, Actinobac- teria, Fusobacteria, and Verrucomicrobia are also present but in reduced numbers [15]. The dynamic nature and the diversity of the microbiome determined to date extends far beyond what researchers expected. We are only beginning to understand how the diversity and distribution of these

or as food products, such as yogurt. Experimentally, several probiotic bacteria

have been tested for health benefits, including Lactobacillus sp. (Firmicutes)

and Bifidobacterium sp. (Actinobacteria), which are both gram-positive

anaerobic bacteria.

6/j.tins.2013.01.005 Trends in Neurosciences, May 2013, Vol. 36, No. 5 305mailto:jfoster@mcmaster.cahttp://dx.doi.org/10.1016/j.tins.2013.01.005

Risk of diseaseNormal

Gut microbiota

GI func�on

CNS circuitry

Immune system

Stress reac�vity

dBarrier func�on

Low-grade inflamma�on

Fat storage/ energy balance

Behavior ea b c

ANS (ENS, vagus)

TRENDS in Neurosciences

Figure 1. Bidirectional communication between gut microbiota and components

of the gut–brain axis influence normal homeostasis and may contribute to risk of

disease. Alterations in gastrointestinal (GI), central nervous system (CNS),

autonomic nervous system (ANS), and immune systems by microbiota may lead

to alterations in (a) fat storage and energy balance; (b) GI barrier function; (c)

general low-grade inflammation (GI and systemic); (d) increased stress reactivity;

and (e) increased anxiety and depressive-like behaviors. Each of these

mechanisms is implicated in the pathophysiology of mood and anxiety

disorders. Abbreviation: ENS, enteric nervous system.

Review Trends in Neurosciences May 2013, Vol. 36, No. 5

prominent phyla contribute to health and disease. To this end, metagenomic population approaches have shown that certain bacterial populations, identified as enterotypes, are shared among groups of humans [18]. Beyond this phyla- level characterization, detailed analyses demonstrate con- siderable individual variability in bacterial content be- tween related and unrelated individuals [1,19]. The microbiome is a dynamic entity, influenced by several factors, including genetics, diet, metabolism, age, geogra- phy, antibiotic treatment, and stress [20–27]. As such, the microbiota profile may be a good representation of the environmental history of the individual and could contrib- ute to individual differences in risk of illness, disease course, and treatment response. These tools are now being used in both human and animal studies, and it will be important to determine how the microbiome in humans differs and/or is similar to that in mice.

Stress and microbiota Alterations in HPA function

Clinically, depressive episodes are associated with dysre- gulation of the hypothalamic–pituitary–adrenal (HPA) axis [28] and resolution of depressive systems with nor- malization of the HPA axis [29,30]. A direct link between microbiota and HPA reactivity was established with the 2004 report that showed an exaggerated corticosterone (CORT) and adrenocorticotrophin (ACTH) response to restraint stress in germ-free (GF) mice when compared with conventionally house-specific pathogen-free (SPF) mice [5]. GF mice have no commensal microbiota and exhibit an undeveloped immune system [10,31–33]. The

306

use of mice raised in a GF environment allows investiga- tors to assess directly the contribution of the microbiota to the development of brain and body systems. This land- mark study showing increased stress reactivity in GF mice [5] was the catalyst for neuroscientists to consider the importance of microbiota in CNS function. Recent work has reproduced these findings, showing enhanced stress reactivity in both male and female mice to a novel envi- ronmental stressor [6].

Over the past few years, it has become clear that gut microbiota play a role in both the programming of the HPA axis early in life and stress reactivity over the lifespan. The stress response system is functionally immature at birth and continues to develop throughout the postnatal period, a developmental period coinciding with intestinal bacterial colonization. Studies using maternal separation in rats show that neonatal stress leads to long-term changes in the diversity and composition of gut microbiota [34,35], which may contribute to long-term alterations in stress reactivity and stress-related behavior observed in these rats. In support of this, concurrent treatment with probio- tics (Lactobacillus sp.) during the early stress period has been shown to normalize basal CORT levels, which are elevated following maternal separation [36]. An indirect role for microbiota in the stress response was recently demonstrated in an animal model of stress-induced social disruption, where it was shown that microbiota are neces- sary for some of the stress-induced changes in inflamma- tion [37]. Stress is known to increase intestinal permeability, thus affording bacteria an opportunity to translocate across the intestinal mucosa and directly ac- cess both immune cells and neuronal cells of the ENS [38,39]. This is therefore a potential pathway whereby the microbiota can influence the CNS via the immune system and ENS in the presence of stress. Intriguingly, a recent study has shown that pretreating rats with probi- otic Lactobacillus farciminis reduced the intestinal perme- ability that typically results from restraint stress and also prevented associated HPA hyper-reactivity [40].

Direct influences on stress circuits

In addition to modulating HPA axis function, microbiota may influence CNS function directly through neuronal activation of stress circuits. Studies using oral administra- tion of food-borne pathogens, Citrobacter rodentium and Campylobacter jejuni, provide evidence that bacteria re- siding in the GI tract can activate stress circuits through activation of vagal pathways [41,42]. During the acute phase of infection with C. jejuni, induction of the neuronal activation marker cFOS was evident in vagal sensory neurons in the absence of a systemic immune response [42]. Central brain regions also showed cFOS activation following oral administration of C. rodentium [41]. cFOS activation of neurons in the paraventricular nucleus of the hypothalamus (PVN) has been shown in GF mice following oral feeding with probiotic Bifidobacterium infantis, en- teropathogenic Escherichia coli, or a mutated noninfec- tious strain of E. coli (DTir) [5]. The cFOS response to E. coli was stronger and accompanied by a robust peripheral cytokine response, suggesting that both neural and im- mune routes contributed to HPA activation in response to

Review Trends in Neurosciences May 2013, Vol. 36, No. 5

infection. By contrast, HPA activation in response to pro- biotic B. infantis and mutated E. coli was not only shorter in duration, but also showed activation of central circuitry in the absence of a systemic immune response [5]. Together these reports provide clear evidence of bottom-up signaling between both pathogenic and commensal bacteria in the GI tract and neurons in central stress circuits.

When considering direct neural routes whereby the microbiota may be influencing the CNS, the ENS must also be included. Sensory neurons of the myenteric plexus in the ENS are the first point of contact for the intestinal microbiota residing in the gut lumen. These sensory neu- rons synapse on enteric motor neurons controlling gut motility. In addition, there is anatomical evidence of close, synaptic-like connections with vagal nerve endings in the gut [43]. Recent work has demonstrated via intracellular recordings that these sensory neurons are less excitable in GF mice than in control SPF mice, an effect that normal- ized after conventionalizing adult GF mice with SPF microbiota [44]. These same neurons have also been shown to become more excitable after feeding rats the probiotic Lactobacillus rhamnosus [45]. These findings are intrigu- ing because they demonstrate altered electrophysiological properties in ENS neurons due to changes in commensal microbiota, providing a potential mechanism whereby the

Table 1. Summary of the impact of altered microbiota on anxiety

Strain Sex Test Main findings

GF versus SPF mice

Swiss Webster

(outbred)

F EPM GF mice showed reduced anxie

arm by GF mice and increased

NMRI (Swiss-type,

outbred)

M OF, L/D and

EPM

GF mice showed reduced anxie

by GF mice in OF; increased tim

time spent in the open arm by

Swiss Webster M L/D GF mice showed reduced anxie

chambers by GF mice

Swiss Webster F L/D GF mice showed no difference

or time spent in light chamber

Reconstitution of microbiota in GF mice

NMRI M EPM and L/D Colonization of GF mice early i

increased time spent in the lig

in conventionalized GF mice co

Swiss Webster M L/D Colonization at 3 weeks of age

Swiss Webster F EPM Colonization of GF mice at 10 w

Swiss Webster

Balb/C

M Step Down Colonization of GF Balb/C mice

behavior; latency to step down

SPF Balb/C mice; colonization

anxiety-like behavior; and laten

microbiota compared with SPF

Effects of infection and gut inflammation on anxiety-like behavior

CF-1 M EPM and

holeboard

Low levels of pathogenic bacte

Balb/C

AKR

M L/D Infection with the parasite Tric

AKR M Step down Dextran sodium sulfate-induce

Influence of probiotics on anxiety-like and depressive-like behaviors

Balb/C M EPM and FST Probiotic treatment reduced an

mice in EPM and FST

Sprague-Dawley M FST Probiotic treatment reversed th

behavior in rats in FST

AKR M Step down Probiotic treatment reversed in

Balb/C

AKR

M L/D Probiotic treatment reversed p

a Abbreviations: F, female; M, male.

brain is informed of changes to the bacterial status of the intestinal lumen.

Gut–brain axis and behavior Evidence gathered from experiments carried out in ani- mals with altered commensal intestinal microbiota, wheth- er GF mice, or conventionally housed animals either treated with probiotics and/or antibiotics or infected with pathogenic bacteria, all indicate that rodent behavioral responses are impacted when the bacterial status of the gut is manipulated. Genetic differences across strains influence behavior and, therefore, it is important to note that work studying the role of microbiota in behavior has been conducted in several strains, including inbred Balb/C, outbred Swiss Webster, NMR1 (a Swiss-type), outbred CF- 1 (not Swiss), and AKR mice. Balb/C mice are readily used by neuroscientists in studies of neuroimmunology and immune–brain communication, including many behavior- al studies. Swiss Webster and NMR1 mice are less often used by neuroscientists in behavioral studies; however, CD1 mice derived from Swiss Webster mice are commonly used. Table 1 provides a detailed summary of the behav- ioral data generated by experiments in which the micro- biota profile of mice or rats has been manipulated. To date, several findings related to microbiota alterations have

-like and depressive-like behaviorsa

Refs

ty-like behavior: increased time spent in the open

number of open-arm entries by GF mice

[4]

ty-like behavior: increased center distance travelled

e spent in the light box by GF mice and increased

GF mice

[2]

ty-like behavior: increased transitions between [6]

in anxiety-like behavior: no difference in transitions

by GF mice compared with SPF mice

[46]

n life reversed EPM phenotype but not L/D phenotype:

ht box by GF mice and no difference in open-arm time

mpared with SPF mice

[2]

reversed L/D transitions [6]

eeks of age; reduced anxiety-like phenotype persisted [3]

with NIH Swiss microbiota reduced anxiety-like

reduced in GF-Balb/C + Swiss microbiota compared with

of GF NIH Swiss mice with Balb/C microbiota increased

cy to step down increased in GF-Swiss + Balb/C

-Swiss mice

[52]

ria administered orally increased anxiety-like behavior [41,42,55]

huris muris increased anxiety-like behavior [57]

d gut inflammation increased anxiety-like behavior [56]

xiety-like and depressive-like behavior in adult Balb/C [53]

e impact of maternal separation on depressive-like [54]

flammatory-induced increase in anxiety-like behavior [56]

arasite-induced increase in anxiety-like behavior [57]

307

Review Trends in Neurosciences May 2013, Vol. 36, No. 5

been replicated in more than one strain and, in particular, the impact of probiotics on behavior has been effective in several strains (Table 1).

GF housing and antibiotic treatment reduced anxiety-

like behavior

Several independent laboratories have demonstrated that adult GF mice have reduced anxiety-like behavior [2–4,6] in the elevated plus maze (EPM), the light/dark test (L/D), and the open field (OF), with the results showing increased exploration of typically aversive zones (open arms in EPM, light chamber in L/D box, and center of the OF); however, one report did not observe changes in transitions or light time in the L/D in GF female mice [46]. Surprisingly, increased basal levels of plasma CORT were observed in GF mice compared with SPF mice [4]. Although it may be unexpected that GF mice show elevated CORT and re- duced anxiety-like behavior, these observations are in line with previous findings showing that anxiety-like behaviors in the EPM are not related to CORT levels [47]. Interest- ingly, reconstitution of microbiota to GF mice early in life was able to normalize EPM behavior and some aspects of L/ D behavior [2,6]. By contrast, in GF mice conventionalized with SPF microbiota in adulthood, the reduced anxiety- like phenotype observed in the EPM persisted [2,3]. These data suggest that there is a critical window during devel- opment where microbiota influence the CNS wiring related to stress-related behaviors (Figure 2).

The use of broad-spectrum antibiotics in drinking water has been reported to reduce significantly the microbial

GF Conv at 10 weeks

GF Conv at 3 weeks

(a) (b)

(c)

GF Conv at birth

Cri�cal period

Postnatal Adolescence

Open arm

Ti m

e sp

en t

(% o

f t ot

al �

m e)

Ti m

e (s

ec )

0 0

200

150

100

50

20

40

SPF Key:

GF

60

Closed arm

Figure 2. Several groups have demonstrated that germ-free (GF) mice, raised without ex

plus maze (EPM) revealed reduced anxiety-like behavior in GF mice compared with spe

also spent more time in the light side of the light/dark (L/D) box and significantly less tim

GF mice early in life normalizes anxiety-like behavior. GF mice conventionalized with

behavior, whereas GF mice conventionalized at 10 weeks of age showed reduced anx

adolescence is a critical period where the gut–brain axis influences adult anxiety-like b

308

number and diversity in healthy adult C57Bl/6 [48]. In models of diet-induced obesity and in genetically modified obese (ob/ob) mice, administration of a broad-spectrum antibiotic improved glucose tolerance [49,50], reduced weight gain and fat mass [49] and lowered adipose inflam- matory markers [49]. It has been suggested that the benefit of altering the profile of microbiota in these models results from reducing intestinal permeability and thereby de- creasing inflammatory tone [49,51]. Male adult mice ex- posed to a mixture of antibiotics (neomycin 5 mg/ml and bacitracin 5 mg/ml) together with the antifungal agent, pimaricin, for 7 days showed reduced anxiety-like and increased exploratory behavior in the step-down and L/D tests [52]. The microbiota profile following 1 week of anti- biotic treatment was significantly different from baseline; however, after a 2-week wash-out period, the microbiota profile normalized, as did the behavior [52]. Antibiotic treatment in GF mice had no effect on behavior, supporting the conclusion that the behavioral changes were mediated by the alterations in microbiota. Interestingly, when GF male Swiss Webster mice were colonized with microbiota from SPF Balb/C mice, an increased anxiety-like behavior was observed, reflecting the behavioral phenotype that is readily observed in SPF Balb/C mice [52]. In the reverse experiment, GF Balb/C mice that received microbiota from SPF Swiss Webster mice showed a reduction in anxiety- like behavior, similar to that seen in SPF Swiss Webster mice. The behavioral differences observed in these recon- stitution experiments were associated with distinct strain- specific microbiota profiles [52].

Light Dark

Adult

Reduced anxiety-like behavior (EPM & L/D)

Normal anxiety-like behavior (L/D transi�ons)

Normal anxiety-like behavior (EPM, not L/D*)

SPF Key:

GF

TRENDS in Neurosciences

posure to microbes, show reduced anxiety-like behavior. (a) Testing in the elevated

cific pathogen free (SPF) mice. (Values are means +/– S.E.M., *P<0.05.) (b) GF mice

e in the dark side (values are means +/– S.E.M., *P<0.05). (c) Conventionalization of

SPF feces at birth (EPM not L/D) or at 3 weeks of age showed normal anxiety-like

iety-like behavior similar to that of adult GF mice [2,3,6]. These data suggest that

ehavior. Reproduced, with permission, from [4] (a) and [2] (b).

Experimental manipula�on

Gut Inflamma�on

Pathogenic bacteria, systemic immune response

Food-borne pathogen, no systemic inflamma�on

Probio�c treatment

An�bio�c treatment

Germ-free mice

High inflammatory

status

Low inflammatory

status

Increased anxiety-like behaviors

Low trait

anxiety

TRENDS in Neurosciences

Figure 3. Microbiota may play a role in the relation between inflammation and

anxiety-like behaviors. Several reports show that experimental manipulations that

alter intestinal microbiota impact anxiety-like behavior. In relation to this, the

observed behavioral changes relate to inflammatory status and are associated with

differences in the microbiota profile in the gastrointestinal tract. This figure is

based on data across many animal studies and represents generalized trends in

these studies [2–4,6,41,42,52–57,80].

Review Trends in Neurosciences May 2013, Vol. 36, No. 5

Probiotics influence anxiety-like and depressive-like

behaviors

A recent study has demonstrated that feeding healthy male Balb/C mice L. rhamnosus decreased anxiety-like and depressive-like behaviors in the EPM, forced swim test (FST), and OF [53]. The probiotic-treated group showed increased entries into the open arms of the EPM, spent less time immobile in the FST, and increased entries and time spent in the center of the OF. In a similar study, adult rats that had undergone maternal separation in the neonatal period showed a reduction in depressive- like symptoms after treatment with probiotic B. infantism, a behavioral effect that was also observed following anti- depressant (citalopram) treatment [54].

Infection and gut inflammation increase anxiety-like

behavior

Exposure to a subpathogenic infection of C. jejuni in- creased anxiety-like behavior measured in the EPM 2 days after infection, which was notable given the absence of an immune response in the periphery [55]. Two additional studies with C. rodentium and C. jejuni showed increased anxiety-like behavior 8 h post-infection, again with no difference in plasma cytokine levels or intestinal inflam- mation compared with control mice [41,42]. These studies show that the presence of pathogenic bacteria in the GI tract, in the absence of a systemic immune response, can increase anxiety-like behavior.

In experiments that result in increased GI inflamma- tion, there are notable increases in anxiety-like behavior [56,57]. Mice with Trichuris muris showed GI inflamma- tion and related increased anxiety-like behavior when were tested in both the L/D test and step-down test [57]. Treatment with the probiotic Bifidobacterium longum was able to normalize anxiety-like behavior in infected mice [57]. In a well-established mouse model of colitis (GI inflammatory disease), animals treated with dextran sodi- um sulfate (DSS) show GI inflammation and increased anxiety-like behavior; however, mice pretreated with DSS showed a reduction of anxiety-like symptoms after treatment with probiotic B. longum [56].

Behavioral studies suggest that inflammatory state

influences behavior

The studies described above suggest that increased inflam- mation is associated with increased anxiety-like behavior. This relation observed across many studies is summarized in Figure 3. Of note, animal studies show that probiotic treatment can reverse inflammation-related increased anxiety-like behavior [56,57]. Additional animal studies with a neuroscience focus and clinical studies in psychiat- ric populations are needed in the area of probiotic treat- ment. Importantly, recent progress has resulted in the availability of tools to study microbiota in clinical popula- tions [58], and we expect that this area of research will continue to expand in the immediate future.

Clinical evidence of probiotic use for mood and anxiety symptoms to date Although the use of probiotics in animal studies has con- sistently shown an impact on anxiety- and depressive-like

behaviors, there is little published work concerning the effects of probiotics on depression or anxiety symptoms in humans. In the limited work that does exist, however, there is evidence that probiotics have similar antidepres- sive and anxiolytic effects as those observed in preclinical studies. In a double-blind, placebo-controlled, randomized parallel group clinical trial, healthy subjects were given a mixture of probiotics containing Lactobacillus helveticus R0052 and B. longum R0175 or placebo for 30 days and then evaluated. Using various questionnaires designed to assess anxiety, depression, stress, and coping mechanisms, the probiotic treatment group demonstrated significantly less psychological distress than did matched controls [59]. Similarly, in another double-blind, placebo-controlled tri- al, healthy subjects were fed either a probiotic-containing milk drink or placebo control for 3 weeks, with mood and cognition assessed before treatment and after 10 and 20 days of consumption. Subjects who initially scored in the lowest third for depressed mood showed significant im- provement in symptoms after probiotic treatment [60]. Chronic fatigue syndrome (CFS) is a functional somatic disorder that is frequently comorbid with anxiety and GI disturbance, and previous work suggested that these patients also demonstrate an altered microbial profile in the gut [61]. In a pilot study, patients with CFS receiving Lactobacillus casei daily for 2 months showed significantly fewer anxiety symptoms than did the placebo group in the Beck Depression & Anxiety Inventories [62]. Although these clinical studies examining the impact of probiotics on mood and anxiety are in the early stages and, to date, are limited to studies in nonpsychiatric patients, the results point us in a promising direction whereby intestinal bacteria could be targeted for their therapeutic potential in mood and anxiety disorders.

Gut–brain axis and neurochemistry Bidirectional communication between gut microbiota and components of the gut–brain axis influence normal

309

Box 1. Outstanding questions

� How do sex differences influence microbiota–brain communica- tion?

To date, alterations in microbiota have resulted in sex-dependent

changes in molecular signaling in the CNS [6,53]; however,

associated changes in behavior have not been identified. Sex

differences are of particular importance because women are twice

as likely as men to suffer from anxiety and depression [81–83].

The challenge going forward is to link sex differences in behavior

to related neurobiological substrates.

� Do microbiota influence learning and memory? A few studies have shown an association between microbiota,

learning, and memory [46,84]. It will be important to expand this

area of research, particularly related to the role of microbiota in

normal healthy CNS development of cognition and in childhood

learning disorders.

� What is the impact of gut microbiota on CNS development? The use of antibiotics in children influences the profile of microbiota

present [20], and yet the impact of early life antibiotic treatment on

CNS development is not known. Importantly, childhood and

adolescence may represent the periods when microbiota structure

and function are the most dynamic and, therefore, it is timely and

necessary to study how gut–brain interactions influence healthy

brain development and risk of mental illness.

� Does the gut–brain axis play a role in childhood neurodevelop- mental disorders, such as autism spectrum disorder (ASD)?

Several studies have now reported changes in microbiota profile

in patients with ASD [85–91]. Although this area of research is new

and consensus across studies has not yet been established, this is

clearly an emerging area of interest. Studies considering possible

mechanisms for gut–brain communication in autism suggest that

an altered metabolic phenotype in association with microbiota

dysbiosis contributes to ASD [90,92], pointing to the importance

of metabolomics in the study of how microbiota may influence

the brain.

� How important are microbiota to CNS function in patient populations?

Future work is needed to determine whether behavioral changes

in animal studies related to microbiota translate to the clinic,

specifically in psychiatric patient populations. This work may also

consider how microbiota influence personality in humans. Do

pharmacotherapies influence the microbiome and are adverse

effects from these treatments, such as weight gain, related to gut

microbiota dysbiosis?

Review Trends in Neurosciences May 2013, Vol. 36, No. 5

homeostasis and may contribute to risk of disease through alterations in GI, CNS, ANS, and immune systems (Figure 1). A critical question facing neuroscientists is whether changes in behavior mediated by microbiota are a result of long-term changes in central signaling systems. To date, investigators have provided evidence that both neuroplasticity-related systems and neuro- transmitter systems are influenced by the gut–brain axis.

Brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, influences many processes, such as the survival and differentiation of neurons, formation of functional synapses, and neuroplasticity during development and in adulthood [63–65]. Changes in hippocampal BDNF mRNA and protein have been noted in relation to the gut–brain axis. In infection models known to lead to alterations in the microbiota profile, reduced expression of hippocampal BDNF mRNA or protein was associated with increased anxi- ety-like behaviors [52,57]. Reversal of behavioral changes by probiotic treatment in these studies was associated with a return to control levels of BDNF expression [52,57]. This work is consistent with previ- ous work linking stress to reduced hippocampal BDNF expression and restoration of normal levels following administration of antidepressants [66,67].

In the case of low levels of anxiety, as observed in GF mice, the reports related to hippocampal BDNF are varied. BDNF protein levels, measured by ELISA, were reduced in the hippocampus and cortex of male GF mice compared with SPF. By contrast, an increase in BDNF mRNA spe- cifically in the dentate gyrus of the hippocampus of female GF mice has been reported [4]. A recently released report showed that a decrease in hippocampal BDNF mRNA expression was observed only in male GF mice. In female GF mice, a qualitative increase in BDNF mRNA expres- sion was present, suggesting that BDNF expression differ- ences are related to sex. A limitation to a broader interpretation of these results is the mismatch between sex differences in this molecular readout and the reduced anxiety-like behavior that is observed in both male and female GF mice. Although the importance of sexual dimor- phism to CNS function and behavior is evident, determin- ing the precise roles for various sex-specific factors will require additional study.

GABAergic signaling

GABA is a major inhibitory neurotransmitter in the CNS, and dysfunctions in GABA signaling are linked to anxiety and depression [68]. Interestingly, Lactoba- cillus and Bifidobacterium bacteria are capable of me- tabolizing glutamate to produce GABA in culture [69,70]. In vivo feeding of L. rhamnosus to mice, noted above to influence anxiety- and depressive-like beha- viors, also altered central expression of GABA receptors in key CNS stress-related brain regions. Importantly, in these healthy mice, CNS effects on gene expression and behavioral effects may be mediated by the vagus nerve, because vagotomized mice did not show behavioral or CNS changes [53].

310

Serotonergic signaling

The serotonergic system is recognized as a major biological substrate in the pathogenesis of mood disorders [71,72], and pharmacological and genetic studies also provide evi- dence for the role of serotonergic signaling molecules in the neurobiology of anxiety [73–79]. Increased serotonin turn- over and altered levels of related metabolites in the stria- tum of GF mice [2] and hippocampus [6] have been reported. At the level of gene expression, increased hippo- campal expression of 5-hydroxytryptamine 1A (5HT1A) receptor mRNA [3] and 5HT2C receptor mRNA [2] has been observed. Together, these initial studies show an association between microbiota and serotonin signaling; however, studies are needed to provide a better under- standing of how changes in serotonergic signaling, periph- eral [6] and central, might influence neural function. In particular, given that microarray profiling revealed altered gene expression in a cluster of genes functionally related to synaptic long-term potentiation [2], there is a clear need for physiology experiments to determine the impact of micro- biota on neurotransmission.

Review Trends in Neurosciences May 2013, Vol. 36, No. 5

Concluding remarks Significant progress has been made over the past decade in recognizing the importance of gut microbiota to brain function. Key findings show that stress influences the composition of the gut microbiota and that bidirectional communication between microbiota and the CNS influ- ences stress reactivity. Several studies have shown that microbiota influence behavior and that immune challenges that influence anxiety- and depressive-like behaviors are associated with alterations in microbiota. Emerging work notes that alterations in microbiota modulate plasticity- related, serotonergic, and GABAergic signaling systems in the CNS. Going forward, there is a significant opportunity to consider how the gut–brain axis and, in particular, new tools will allow researchers to understand how dysbiosis of the microbiome influences mental illness. Neuroscientists, armed with the results to date in this area, are well positioned to tackle outstanding questions (Box 1) and develop innovative approaches to prevent and treat stress-related disorders, including anxiety and depression.

Acknowledgments Operating funds from the National Science and Engineering Research Council of Canada (NSERC, to J.A.F.), and equipment funds from Canadian Foundation for Innovation (to J.A.F.) contributed to this project. Graduate stipend support (to K.A.N.) was provided by Ontario Graduate Scholarship and Ontario Graduate Scholarship in Science and Technology.

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  • Gut-brain axis: how the microbiome influences anxiety and depression
    • Introduction
    • Overview of the microbiome
    • Stress and microbiota
      • Alterations in HPA function
      • Direct influences on stress circuits
    • Gut-brain axis and behavior
      • GF housing and antibiotic treatment reduced anxiety-like behavior
      • Probiotics influence anxiety-like and depressive-like behaviors
      • Infection and gut inflammation increase anxiety-like behavior
      • Behavioral studies suggest that inflammatory state influences behavior
    • Clinical evidence of probiotic use for mood and anxiety symptoms to date
    • Gut-brain axis and neurochemistry
      • Brain-derived neurotrophic factor
      • GABAergic signaling
      • Serotonergic signaling
    • Concluding remarks
    • Acknowledgments
    • References

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By Chris Iliades, MD

Medically reviewed by Pat F. Bass III, MD, MPH

Have you ever “choked” under stress? Did you ever have to make a “gut-wrenching”

decision under pressure? If so, then you know how stress can affect your digestion.

“Stress can affect every part of the dige stiv e syste m,” says Kenneth Koch, MD, professor

of medicine, section on gastroenterology and medical director of the Digestive Health Center

at Wake Forrest University Baptist Medical Center in Winston-Salem, N.C. “Johann Wolfgang

von Goethe, the great German writer and philosopher, believed that the gut was the seat of

all human emotions.”

What Happe ns to Dige stion Unde r Stre ss?

Dige stion is controlled by the enteric nervous system, a system composed of hundreds of

millions of nerves that communicate with the central nervous system. When stress activates

the “flight or fight” response in your central nervous system, digestion can shut down

because your central nervous system shuts down blood flow, affects the contractions of your

digestive muscles, and decreases secretions needed for digestion. Stress can cause

inflammation of the gastrointestinal system, and make you more susceptible to infection.

“Stress can cause your esophagus to go into spasms. It can increase the acid in your

stomach causing indigestion. Under stress, the mill in your stomach can shut down and make

you feel nauseous. Stress can cause your colon to react in a way that gives you diarrhea or

constipation. We are all familiar with the athlete or the student who has to rush to the

bathroom before the big game or the big exam,” explains Koch. “Although stress may not

cause stomach ulcers, celiac disease, or inflammatory bowel disease, it can make these and

other diseases of digestion worse.”

Ke e ping Stre ss Unde r Control to Aid Dige stion

“One of the best ways to manage stress and maintain he althy dige stion is moderate

exercise,” Koch says. Physical activity relieves tension and stimulates the release of brain

chemicals called endorphins that relieve stress and improve your mood. Other stress

reducers include:

Re laxation the rapy. People who have stress-related problems with digestion often

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benefit from relaxation therapies such as yoga, meditation, hypnosis, progressive

muscle relaxation, mental imaging, biofeedback, and even music. One study found

that people with irritable bowel syndrome found significant relief from pain, bloating,

and diarrhea from a relaxation therapy called Relaxation Response, which was

developed by a researcher at the Harvard Medical School.

Talk the rapy. Talking to friends or loved ones about your stress can be a big help,

and actual talk therapy that involves working with a therapist can be particularly

valuable. A trained therapist can help you find better ways to deal with your stress.

Mental health professionals use cognitive behavioral therapy to teach people new

coping skills. In a recent study of people with irritable bowel syndrome, 70 percent

saw improvement in their symptoms after 12 weeks of cognitive behavioral therapy.

Die t and dining. Eating foods that are bad for your digestion can be a cause of

stress. Don’t deal with stress by overeating or binging on junk food. “Your digestive

system appreciates a he althy, we ll-balance d die t. Avoid extremes of sugar, fat,

and alcohol,” advises Koch. “Consider dining, not refueling, when it comes to eating.

A relaxed, unhurried, candle-light atmosphere is good for digestion.”

Limit stre ssors. Resist easing stress by smoking or using alcohol. Relying on drugs

to deal with stress can also be tough on digestion. “People who are constantly

popping over-the-counter non-steroidal anti-inflammatory medications for stress

headaches can be damaging their digestive tract,” warns Koch. Avoid too much

coffee and soft drinks that give you a jolt of caffeine and sugar.

A certain amount of stress is unavoidable. We all have to deal with it. It’s important to know

that stress can upset healthy digestion and make many digestive diseases worse. If you are

having symptoms of stress that are interfering with digestion, talk to your doctor. You may

have a digestive problem that needs treatment. If stress management is the problem, your

doctor can refer you to a mental health professional who can help.

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content/enforced/45566-ANT100-WIN2015-1/ptsd-and-cortisol.pdf

Many researchers have studied how trauma and posttraumatic stress disorder

(PTSD) impact cortisol, a primary stress hormone. Although cortisol

dysregulation is common in the general population, PTSD appears to hasten

cortisol imbalance and its extensive consequences, making it an important area of

continued study. The following paper provides a brief review of the documented

relationship between traumatic stress and cortisol, as well as an overview of how

cortisol responds to clinical treatments targeting PTSD.

The stress response

In his seminal work, Hans Selye 1 defined stress as “the non-specific response of the

body to any demand placed upon it” and noted that the body’s reaction to stress (also

referred to as the general adaptation syndrome or the stress response) can be activated

by both actual and perceived demands.

When a stressor is identified, the hypothalamic-pituitary-adrenal (HPA) axis activates

the “fight-or-flight” response. Cortisol, released by the adrenal gland, plays a key role in

directing physiological and metabolic processes away from long-term management to

immediate survival (e.g., increases in heart rate, decreases in digestion, alterations in

immune functioning) and then works together with dehydroepiandrosterone (DHEA) to

bring the body back to a normal state 2 . For a detailed review of the stress response,

please refer to Selye 3 .

Cortisol dysregulation and its consequences

Prolonged activation of the stress response can compromise the body’s internal stability,

resulting in HPA axis dysregulation and alterations in cortisol levels. Chronic illness

and disease can then ensue due to cortisol’s impact on the immune system. Enhanced

cortisol activity suppresses cellular immunity, increasing susceptibility to infection and

The Relationship between Traumatic Stress, PTSD and Cortisol

By Eileen Delaney, PhD

Naval Center for Combat & Operational Stress Control

2

neoplasm (abnormal growth of tissue), while low cortisol levels stimulate pro-

inflammatory cytokines, which can lead to autoimmune diseases and malignancy 2 .

Endocrine disorders can be another consequence of abnormal cortisol functioning. High

levels of cortisol decrease the liver’s sensitivity to insulin (i.e., insulin resistance),

which increases glucose levels in the blood. If left untreated, high blood glucose can

lead to kidney, neurological and cardiovascular damage 4 .

Mental health and cognitive problems may also develop from cortisol dysregulation.

Hypercortisolism is associated with obsessive-compulsive disorder, panic disorder and

melancholic depression, while hypocortisolism has been linked to depressed mood,

chronic pain, sleep disturbances and fatigue 2 . Additionally, cortisol’s ability to bind to

receptors in the hippocampus (the brain region involved in memory) can impact

memory and consciousness. An over-production of cortisol can shrink and cause

atrophy of the hippocampus, leading to memory difficulties 5 . Severe hippocampal

atrophy may result in periods of dissociation 6 .

Cortisol and PTSD

It is well documented that individuals with PTSD have altered cortisol levels, yet the

direction of impairment (i.e., too high or too low) is mixed. Yehuda and colleagues 7

showed that chronic PTSD was associated with lowered cortisol activity compared to

those without a PTSD diagnosis and suggested that chronically high stress levels may

exhaust the HPA axis. Other studies have found higher cortisol activity in those with

PTSD. One research team found that compared to controls, Vietnam combat veterans

with PTSD had higher overall cortisol levels 8 . Another study documented that Croatian

combat veterans had fewer glucocorticoid receptors (receptors that cortisol binds to)

compared to healthy controls 9 , which could also contribute to higher levels of

circulating cortisol.

One study found that child abuse victims with PTSD experienced enhanced cortisol

activity in response to exposure to traumatic reminders, bringing researchers to

conclude that low levels of baseline cortisol may compensate for periods of higher

cortisol levels that accompany stress 10

. Still, some researchers have documented normal

3

cortisol levels in a sample that consisted of individuals diagnosed with PTSD from

varying types of events (e.g., childhood trauma, domestic violence, war) 11

.

Family and individual factors are important to consider when examining the relationship

between PTSD and cortisol activity. Yehuda and colleagues 12

documented lower

cortisol excretion in children of holocaust survivors with PTSD compared to healthy

controls. Further, children who had two parents with PTSD had lower levels compared

to those who only had one parent with PTSD. The authors note that the impact of

parental PTSD on the child’s cortisol level could be related to both biological

mechanisms and the environment in which the child is raised (e.g., parental neglect).

Avoidance, a hallmark symptom of PTSD, may also play a significant role in the

relationship between cortisol and PTSD. Research has shown that the engagement-

nonengagement style of coping influences cortisol levels 13,14

and that nonengagement

has been associated with low levels of cortisol 15

. These findings may explain some of

the variability in cortisol findings across PTSD populations. Those patients who avoid

and withdraw to a greater extent may have lower cortisol levels. Additionally, cortisol

levels vary throughout the day and in different situations within the same individual 16

.

Thus, times of avoidance, withdrawal and isolation may be associated with lower

cortisol levels, while re-experiencing and hyperarousal are related to enhanced cortisol

activity.

Cortisol and PTSD treatment

Given the neuroendocrine dysregulation in those with PTSD, researchers have begun to

study the impact of PTSD treatments on cortisol levels. Olff, de Vries, Guzelcan, Assies

and Gersons 17

examined cortisol response to trauma-based cognitive-behavioral therapy

(CBT) in 21 individuals with PTSD due to civilian traumas. They found that successful

treatment, assessed by the Structured Interview for PTSD (SI-PTSD) and self-report

symptom measures (i.e., Impact of Event Scale [IES], Beck Depression Inventory

[BDI]), was associated with enhanced levels of basal cortisol and DHEA at post-

treatment. However, the improvements in hormonal measures were only seen when

depression symptoms were included in the model.

4

Using a sample of 28 trauma survivors from the 9/11 attack of the World Trade Center,

Yehuda and colleagues 18

monitored individuals’ cortisol levels as they participated in

psychological treatment. Basal cortisol and PTSD severity (assessed by the

Posttraumatic Stress Symptom-Interview [PSSI] and the PTSD Symptom Scale-Self

Report [PSS-SR]) were collected before and after treatment. At pre-treatment, cortisol

indicators (5-alpha reductase activity, total glucocorticoids) were lower for those who

had higher avoidance scores but for no other symptom cluster (i.e., re-experiencing,

hyperarousal). At post-treatment, 5-alpha reductase activity was significantly correlated

with all three PTSD symptom clusters, as well as total severity scores. Overall, these

findings indicate that those who were highly avoidant showed lowered cortisol activity,

and successful treatment increased cortisol levels.

Gerardi, Rothbaum, Astin and Kelly 19

were the first researchers to use a randomized

control design when examining cortisol response to PTSD treatment. Sixty women with

PTSD were randomly assigned to prolonged exposure (PE), eye-movement

desensitization and reprocessing (EMDR) or waitlist. Measures were taken at three time

points: at baseline, immediately after session 3 (first exposure session) and immediately

after session 9 (last exposure session). Results showed that treatment response (i.e., at

least a 50 percent reduction in PTSD symptoms assessed via the Clinician-Administered

PTSD Scale [CAPS]) was associated with decreased cortisol levels. Cortisol

measurements taken immediately after exposure sessions may explain why effective

treatment was related to lower cortisol levels, whereas previous studies documented

increased cortisol in response to treatment.

Summary and future directions

Cortisol plays a key role in physical and mental well-being. Research has shown that

those with chronic PTSD often have dysregulated basal cortisol levels, yet individual

and family factors (i.e., extent of isolation, parental PTSD) may also play a role.

Investigators have begun to study the impact of PTSD treatment on cortisol activity and

have found that clinical treatments have the potential to stabilize cortisol levels.

However, a significant limitation in this line of study is the lack of prospective designs.

Since cortisol activity prior to the traumatic event is often unknown, causation cannot be

5

established. Although it is often assumed that traumatic events alter cortisol levels, it is

also possible that trauma survivors who develop PTSD had low cortisol activity before

the event, which increased their vulnerability to developing the disorder. Another

limitation is the various ways in which cortisol is assessed, making these measurements

difficult to compare without the use of meta-analytic strategies. With continued

research, further inquiry to how cortisol interacts with trauma may hold promise in

helping improve detection and treatment of PTSD and other trauma-related problems.

References:

1. Selye H. The general adaptation syndrome and diseases of adaptation. The

Journal of Clinical Endocrinology and Metabolism. 1936; 6(2):117-230.

2. Guilliams TG, Edwards L. Chronic stress and the HPA axis: Clinical assessment

and therapeutic considerations. A Review of Natural & Nutraceutical Therapies

for Clinical Practice. 2010; 9(2):1-12.

3. Selye H. Stress and the general adaptation syndrome. British Medical Journal.

1950; 1:1383 – 1392.

4. Lansang MC, Hustak LK. Glucocorticoid-induced diabetes and adrenal

suppression: How to detect and manage them. Cleveland Clinic Journal of

Medicine. 2011; 78(11):748-756.

5. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens, MJ, Southwick SM,

Nemeroff, CB, Charney, DS. Elevated CSF corticotropin-releasing factor

concentrations in posttraumatic stress disorder Am J Psychiatry. 1997; 154(5):

624-629.

6. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric

disorders. Archives of General Psychiatry. 2000; 57:925-935.

7. Yehuda R, Bierer LM, Schmeidler J, Aferiat DH, Breslau I, Dolan S. Low

cortisol and risk for PTSD in adult offspring of Holocaust survivors. American

Journal of Psychiatry. 2000; 157:1252–1259.

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8. Pitman R, Orr S. Twenty-four-hour urinary cortisol and catecholamine excretion

in combat-related posttraumatic stress disorder. Biological Psychiatry. 1990;

27(2):245-247.

9. Gotovac K, Sabioncello A, Rabatic S, Berki T, Dekaris D. Flow cytometric

determination of glucocorticoid receptor (GCR) expression in lymphocyte

subpopulations: Lower quantity of GCR in patients with post-traumatic stress

disorder (PTSD). Clin Exp Immunol. 2003; 131:335–339.

10. Elzinga BM, Schmahl, CG, Vermetten E, van Dyck R, Bremner JD. Higher

cortisol levels following exposure to traumatic reminders in abuse-related PTSD.

Neuropharmacology. 2003; 28:1656 – 1666.

11. Wheler GH, Brandon D, Clemons A, Riley C, Kendall J, Loriaux DL, Kinzie JD.

Cortisol production rate in posttraumatic stress disorder. The Journal of Clinical

Endocrinology and Metabolism. 2006; 91(9):3486-3489.

12. Yehuda R, Halligan SL, Bierer, LM. Cortisol levels in adult offspring of

Holocaust survivors: Relation in PTSD symptom severity in the parent and child.

Psychoneuroendocrinology. 2002; 27: 171-180.

13. Price DB, Thaler M, Mason JW. Preoperative emotional states and adrenal

cortical activity. Arch Gen Psychiatry. 1957; 77:646–56.

14. Singer MT. Engagement-involvement: a central phenomenon in

psychophysiological research. Psychosom Med. 1974; 36:1–17.

15. Mason JW, Wang S, Yehuda R, Riney S, Charney, DS, Southwick S.

Psychogenic lowering of urinary cortisol levels linked to increased emotional

numbing and a shame-depressive syndrome in combat-related posttraumatic

stress disorder. Psychosomatic Medicine. 2001; 63:387-401.

16. Weitzman ED, Fukushima D, Nogeire C, Roffwarg H, Gallagher TF, Hellman L.

Twenty-four-hour pattern of the episodic secretion of cortisol in normal subjects.

Journal of Clinical Endocrinology Metabolism. 1971; 33:14–22.

7

17. Olff M, de Vries G, Guzelcan Y, Assies J, Gersons B. Changes in cortisol and

DHEA plasma levels after psychotherapy for PTSD. Psychoneuroendocrinology.

2007; 32:619-626.

18. Yehuda R, Bierer LM, Sarapass C, Makotkine L, Andrew R, Seckl J. Cortisol

metabolic predictors of response to psychotherapy for symptoms of PTSD in

survivors of the World Trade Center attacks on September 11, 2001.

Psychoneuroendocrinology. 2009: 34(9):1304-1313.

19. Gerardi M, Rothbaum BO, Astin MC, Kelly M. Cortisol response following

exposure treatment for PTSD in rape victims. Journal of Aggression,

Maltreatment, and Trauma. 2010; 19(4):349-356.

content/enforced/45566-ANT100-WIN2015-1/stress and female reproduction.pdf

Journal of Reproductive Immunology 62 (2004) 61–68

Review

Stress and the female reproductive system

S.N. Kalantaridoua, A. Makrigiannakisb, E. Zoumakisc, G.P. Chrousosc,d,∗

a Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology, University of Ioannina, School of Medicine, Panepistimiou Avenue, 45500 Ioannina, Greece

b Department of Obstetrics and Gynecology, University of Crete, School of Medicine, 7110 Heraklion, Greece c Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human

Development, National Institutes of Health, Building 10, Room 9D42, Bethesda, MD 20892-1583, USA d 1st Department of Pediatrics, University of Athens, School of Medicine, Athens, Greece

Received in revised form 25 September 2003; accepted 25 September 2003

Abstract

The hypothalamic–pituitary–adrenal (HPA) axis, when activated by stress, exerts an inhibitory effect on the female reproductive system. Corticotropin-releasing hormone (CRH) inhibits hypothalamic gonadotropin-releasing hormone (GnRH) secretion, and glucocorticoids inhibit pituitary luteiniz- ing hormone and ovarian estrogen and progesterone secretion. These effects are responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome. In addition, corticotropin-releasing hormone and its receptors have been identified in most female reproductive tissues, including the ovary, uterus, and placenta. Furthermore, corticotropin-releasing hormone is secreted in peripheral inflammatory sites where it exerts inflammatory actions. Repro- ductive corticotropin-releasing hormone is regulating reproductive functions with an inflammatory component, such as ovulation, luteolysis, decidualization, implantation, and early maternal toler- ance. Placental CRH participates in the physiology of pregnancy and the onset of labor. Circulating placental CRH is responsible for the physiologic hypercortisolism of the latter half of pregnancy. Postpartum, this hypercortisolism is followed by a transient adrenal suppression, which may explain the blues/depression and increased autoimmune phenomena observed during this period. © 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Decidualization; Implantation; Luteolysis; Maternal tolerance; Ovulation; Parturition; Reproductive corticotropin-releasing hormone; Stress

∗ Corresponding author. Tel.:+1-301-496-5800; fax:+1-301-402-0884. E-mail address: chrousog@mail.nih.gov (G.P. Chrousos).

0165-0378/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jri.2003.09.004

62 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68

1. Introduction

The hypothalamic–pituitary–adrenal (HPA) axis exerts an inhibitory effect on the female reproductive system (Chrousos et al., 1998). In addition, the hypothalamic neuropeptide corticotropin-releasing hormone (CRH) and its receptors have been identified in most fe- male reproductive tissues, including the ovary, uterus, and placenta. Furthermore, CRH is secreted in peripheral inflammatory sites where it exerts strong inflammatory actions. Thus, “reproductive” CRH is a form of “tissue” CRH (CRH found in peripheral tissues), analogous to the “immune” CRH (Chrousos, 1995). “Reproductive” CRH is regulating key reproductive functions with an inflammatory component, such as ovulation, luteolysis, implantation, and parturition.

2. Interactions between the hypothalamic–pituitary–adrenal axis and the female reproductive system

The hypothalamic–pituitary–adrenal axis along with the arousal and autonomic nervous systems constitute the stress system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis, and increases its chance for survival (Chrousos and Gold, 1992).

The principal regulators of the HPA axis are CRH and arginine–vasopressin (AVP), both produced by parvicellular neurons of the paraventricular nucleus of the hypothalamus into the hypophyseal portal system (Chrousos and Gold, 1992). CRH and AVP synergistically stimulate pituitary adrenocorticotropic hormone (ACTH) secretion and, subsequently, cor- tisol secretion by the adrenal cortex.

The female reproductive system is regulated by the hypothalamic–pituitary–ovarian axis. The principal regulator of the hypothalamic–pituitary–ovarian axis is gonadotropin-releasing hormone (GnRH), produced by neurons of the preoptic and arcuate nucleus of the hypotha- lamus into the hypophyseal portal system (Ferin, 1996). GnRH stimulates pituitary follicle stimulating and luteinizing hormone secretion and, subsequently, estradiol and progesterone secretion by the ovary.

The HPA axis, when activated by stress, exerts an inhibitory effect on the female repro- ductive system (Table 1). Corticotropin-releasing hormone and CRH-induced proopiome- lanocortin peptides, such as�-endorphin, inhibit hypothalamic GnRH secretion (Chen et al., 1992). In addition, glucocorticoids suppress gonadal axis function at the hypothalamic, pi- tuitary and uterine level (Sakakura et al., 1975; Rabin et al., 1990). Indeed, glucocorticoid

Table 1 Effect of the hypothalamic–pituitary–adrenal axis on the female reproductive system

Hypothalamic–pituitary–adrenal axis Effect on the female reproductive system

CRH Inhibition of GnRH secretion �-Endorphin Inhibition of GnRH secretion Cortisol Inhibition of GnRH and LH secretion, inhibition of ovarian estrogen

and progesterone biosynthesis, inhibition of estrogen actions

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68 63

administration significantly reduces the peak luteinizing hormone response to intravenous GnRH, suggesting an inhibitory effect of glucocorticoids on the pituitary gonadotroph (Sakakura et al., 1975). Furthermore, glucocorticoids inhibit estradiol-stimulated uterine growth (Rabin et al., 1990).

These effects of the HPA axis are responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome (Chrousos et al., 1998).

On the other hand, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system (Vamvakopoulos and Chrousos, 1993), which may explain women’s mood cycles and manifestations of autoimmune/allergic and inflammatory diseases that follow estradiol fluctuations. Indeed, suicide attempts and allergic bronchial asthma attacks significantly increase when the plasma estradiol level reaches its lowest level, i.e. during the late luteal and early follicular phases of the menstrual cycle (Fourestie et al., 1986; Skobeloff et al., 1996).

3. “Reproductive” corticotropin-releasing hormone

CRH and its receptors have been identified in several female reproductive organs, in- cluding the ovaries, the endometrial glands, decidualized endometrial stroma, placental tro- phoblast, syncytiotrophoblast and decidua (Mastorakos et al., 1994, 1996; Makrigiannakis et al., 1995a; Grino et al., 1987; Clifton et al., 1998; Frim et al., 1988; Petraglia et al., 1992; Jones et al., 1989; Grammatopoulos and Chrousos, 2002). “Reproductive” CRH partici- pates in various reproductive functions with an “aseptic” inflammatory component, such as ovulation, luteolysis, implantation and parturition (Table 2).

Ovarian CRH is primarily found in the theca and stroma and also in the cytoplasm of the ovum (Mastorakos et al., 1993, 1994). Corticotropin-releasing hormone type 1 (CRHR-1)

Table 2 Reproductive corticotropin-releasing hormone, potential physiologic roles and potential pathogenic effects

Reproductive CRH Potential physiologic roles Potential pathogenic effects

Ovarian CRH Follicular maturation Premature ovarian failure (↑ secretion) Ovulation Anovulation (↓ secretion) Luteolysis Corpus luteum dysfunction (↓ secretion) Suppression of female sex steroid production

Ovarian dysfunction (↓ secretion)

Uterine CRH Decidualization Infertility (↓ secretion) Blastocyst implantation Recurrent spontaneous abortion (↓ secretion) Early maternal tolerance

Placental CRH Labor Premature labor (↑ secretion) Maternal hypercortisolism Delayed labor (↓ secretion) Fetoplacental circulation Preeclampsia and eclampsia (↑ secretion) Fetal adrenal steroidogenesis

64 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68

receptors (similar to those of the anterior pituitary) are also detected in the ovarian stroma and theca and in the cumulus oophorus of the graafian follicle. In vitro experiments have shown that CRH exerts an inhibitory effect on ovarian steroidogenesis in a dose-dependent, interleukin (IL)-1-mediated manner (Calogero et al., 1996; Ghizzoni et al., 1997). This finding suggests that ovarian CRH has anti-reproductive actions that might be related to the earlier ovarian failure observed in women exposed to high psychosocial stress (Bromberger et al., 1997). Interestingly, CRH and its receptors have also been identified in Leydig cells of the testis, where CRH exerts inhibitory actions on testosterone biosynthesis (Fabri et al., 1990).

There is no detectable CRH in oocytes of primordial follicles in human ovaries, whereas there is abundant expression of the CRH and CRHR-1 genes in mature follicles, suggesting that CRH may play auto/paracrine roles in follicular maturation (Mastorakos et al., 1993, 1994; Asakura et al., 1997). However, polycystic ovaries present diminished amounts of CRH immunoreactivity, suggesting that decreased ovarian CRH might be related to the anovulation of polycystic ovarian syndrome (Mastorakos et al., 1994). Finally, the concen- tration of CRH is higher in the premenopausal than the postmenopausal ovaries, indicating that ovarian CRH may be related to normal ovarian function during the reproductive life span (Zoumakis et al., 2001).

The human endometrium also contains CRH (Mastorakos et al., 1996; Makrigiannakis et al., 1995a). Epithelial cells are the main source of endometrial CRH, while stroma does not express it, unless it differentiates to decidua (Mastorakos et al., 1996;Makrigiannakis et al., 1995a,b;Ferrari et al., 1995). In addition, CRH receptors type 1 are present in both epithelial and stroma cells of human endometrium (Di Blasio et al., 1997) and in human myometrium (Hillhouse et al., 1993), suggesting a local effect of endometrial CRH. Estro- gens and glucocorticoids inhibit and prostaglandin E2 stimulates the promoter of human CRH gene in transfected human endometrial cells, suggesting that the endometrial CRH gene is under the control of these agents (Makrigiannakis et al., 1996). The endometrial glands are full of CRH during both the proliferative and the secretory phases of the cycle (Mastorakos et al., 1996; Makrigiannakis et al., 1995a). However, the concentration of CRH is significantly higher in the secretory phase, associating endometrial CRH with intrauter- ine phenomena of the secretory phase of the menstrual cycle, such as decidualization and implantation (Zoumakis et al., 2001).

Early in pregnancy, the implantation sites in rat endometrium contain 3.5-fold higher concentrations of CRH compared to the interimplantation regions (Makrigiannakis et al., 1995b). Furthermore, human trophoblast and decidualized endometrial cells express Fas ligand (FasL), a pro-apoptotic molecule. These findings suggest that intrauterine CRH may participate in blastocyst implantation, while FasL may assist with maternal immune tolerance to the semi-allograft embryo. A nonpeptidic CRH receptor type 1-specific an- tagonist (antalarmin) decreased the expression of FasL by human trophoblasts, suggesting that CRH regulates the pro-apoptotic potential of these cells in an auto/paracrine fash- ion (Makrigiannakis et al., 2001). Invasive trophoblasts promoted apoptosis of activated Fas-expressing human T-lymphocytes, an effect potentiated by CRH and inhibited by CRH antagonist. In support of these findings, female rats treated with the CRH antag- onist in the first 6 days of gestation had a dose-dependent decrease of endometrial im- plantation sites and markedly diminished endometrial FasL expression (Makrigiannakis

S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68 65

et al., 2001). Thus, locally produced CRH promotes implantation and maintenance of early pregnancy.

The human placenta contains CRH as well. Placental CRH is produced in syncytiotro- phoblast cells, in placental decidua and fetal membranes (Riley et al., 1991; Jones et al., 1989). Placental CRH expression increases as much as 100 times during the last 6–8 weeks of pregnancy (Frim et al., 1988). The biologic activity of CRH in maternal plasma is at- tenuated by the presence of a circulating CRH binding protein (CRH-BP), produced by the liver and placenta (Challis et al., 1995; Linton et al., 1993). Nevertheless, CRH-BP concentrations decrease during the last 6 weeks of pregnancy, leading to elevations of free CRH (Challis et al., 1995; Linton et al., 1993). Thus, placental CRH is responsible for the hypercortisolism observed during the latter half of pregnancy. This hypercortisolism is followed by a transient suppression of hypothalamic CRH secretion in the postpartum period, which may explain the blues/depression and autoimmune phenomena seen during this period (Chrousos et al., 1998; Magiakou et al., 1996; Elenkov et al., 2001).

Placental CRH induces dilation of uterine and fetal placental vessels through nitric oxide synthetase activation, and stimulation of smooth muscle contractions through prostaglandin F2alpha and E2 production by fetal membranes and placental decidua (Chrousos, 1999; Grammatopoulos and Hillhouse, 1999). Placental CRH secretion is stimulated by glucocor- ticoids, inflammatory cytokines, and anoxic conditions, including the stress of preeclampsia or eclampsia (Chrousos et al., 1998; Robinson et al., 1988; Goland et al., 1995), whereas it is repressed by estrogens (Ni et al., 2002).

CRH may be the placental clock triggering the onset of parturition (McLean et al., 1995; Challis et al., 2000; Majzoub and Karalis, 1999). Of note, experimental data have shown that CRH receptor type 1 antagonism in the sheep fetus, using antalarmin, can delay the onset of parturition (Cheng-Chan et al., 1998).

4. Conclusions

The HPA axis exerts an inhibitory effect on the female reproductive system. CRH inhibits hypothalamic GnRH secretion, whereas glucocorticoids suppress pituitary LH and ovarian estrogen and progesterone secretion and render target tissues resistant to estradiol (Chrousos et al., 1998). The HPA axis is responsible for the “hypothalamic” amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome (Chrousos et al., 1998).

In addition, CRH and its receptors have been identified in female reproductive organs, including the ovaries, the endometrium and the placenta. “Reproductive” CRH partici- pates in various reproductive functions with an inflammatory component (Chrousos et al., 1998). Ovarian CRH participates in the regulation of steroidogenesis, follicular maturation, ovulation and luteolysis. Endometrial CRH participates in the decidualization, blastocyst implantation, and early maternal tolerance. Placental CRH, which is secreted mostly during the latter half of pregnancy, may be responsible for the onset of labor and the physiologic hy- percortisolism seen during this period. This hypercorticolism causes a transient postpartum adrenal suppression, which may explain the blues/depression and autoimmune phenomena of the postpartum period (Magiakou et al., 1996; Elenkov et al., 2001).

66 S.N. Kalantaridou et al. / Journal of Reproductive Immunology 62 (2004) 61–68

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  • Stress and the female reproductive system
    • Introduction
    • Interactions between the hypothalamic-pituitary-adrenal axis and the female reproductive system
    • “Reproductive” corticotropin-releasing hormone
    • Conclusions
    • References

content/enforced/45566-ANT100-WIN2015-1/Understanding the Stress Response – Harvard Health Publications.pdf

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Understanding the stress response

Chronic activation of this survival mechanism impairs health.

For two years in a row, the annual stress survey commissioned by the American Psychological Association has found that about 25% of Americans are experiencing high levels of stress (rating their stress level as 8 or more on a 10-point scale), while another 50% report moderate levels of stress (a score of 4 to 7). Perhaps not surprising, given continuing economic instability in this country and abroad, concerns about money, work, and the economy rank as the top sources of stress for Americans.

Stress is unpleasant, even when it is transient. A stressful situation — whether something environmental, such as a looming work deadline, or psychological, such as persistent worry about losing a job — can trigger a cascade of stress hormones that produce well-orchestrated physiological changes. A stressful incident can make the heart pound and breathing quicken. Muscles tense and beads of sweat appear.

This combination of reactions to stress is also known as the “fight-or-flight” response because it evolved as a survival mechanism, enabling people and other mammals to react quickly to life-threatening situations. The carefully orchestrated yet near-instantaneous sequence of hormonal changes and physiological responses helps someone to fight the threat off or flee to safety. Unfortunately, the body can also overreact to stressors that are not life-threatening, such as traffic jams, work pressure, and family difficulties.

Over the years, researchers have learned not only how and why these reactions occur, but have also gained insight into the long-term effects stress has on physical and psychological health. Over time, repeated activation of the stress response takes a toll on the body. Research suggests that prolonged stress contributes to high blood pressure, promotes the formation of artery-clogging deposits, and causes brain changes that may contribute to anxiety, depression, and addiction. More preliminary research suggests that chronic stress may also contribute to obesity, both through direct mechanisms (causing people to eat more) or indirectly (decreasing sleep and exercise).

Sounding the alarm

The stress response begins in the brain (see illustration). When someone confronts an oncoming car or other danger, the eyes or ears (or both) send the information to the amygdala, an area of the brain that contributes to emotional processing. The amygdala interprets the images and sounds. When it perceives danger, it instantly sends a distress signal to the hypothalamus.

Command centerhttp://www.health.harvard.edu/

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When someone experiences a stressful event, the amygdala, an area of the brain that contributes to emotional processing, sends a distress signal to the hypothalamus. This area of the brain functions like a command center, communicating with the rest of the body through the nervous system so that the person has the energy to fight or flee.

The hypothalamus is a bit like a command center. This area of the brain communicates with the rest of the body through the autonomic nervous system, which controls such involuntary body functions as breathing, blood pressure, heartbeat, and the dilation or constriction of key blood vessels and small airways in the lungs called bronchioles. The autonomic nervous system has two components, the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system functions like a gas pedal in a car. It triggers the fight-or-flight response, providing the body with a burst of energy so that it can respond to perceived dangers. The parasympathetic nervous system acts like a brake. It promotes the “rest and digest” response that calms the body down after the danger has passed.

After the amygdala sends a distress signal, the hypothalamus activates the sympathetic nervous system by sending signals through the autonomic nerves to the adrenal glands. These glands respond by pumping the hormone epinephrine (also known as adrenaline) into the bloodstream. As epinephrine circulates through the body, it brings on a number of physiological changes. The heart beats faster than normal, pushing blood to the muscles, heart, and other vital organs. Pulse rate and blood pressure go up. The person undergoing these changes also starts to breathe more rapidly. Small airways in the lungs open wide. This way, the lungs can take in as much oxygen as possible with each breath. Extra oxygen is sent to the brain, increasing alertness. Sight, hearing, and other senses become sharper. Meanwhile, epinephrine triggers the release of blood sugar (glucose) and fats from temporary storage sites in the body. These nutrients flood into the bloodstream, supplying energy to all parts of the body.

All of these changes happen so quickly that people aren’t aware of them. In fact, the wiring is so efficient that the amygdala and hypothalamus start this cascade even before the brain’s visual centers have had a chance to fully process what is happening. That’s why people are able to jump out of the path of an oncoming car even before they think about what they are doing.

As the initial surge of epinephrine subsides, the hypothalamus activates the second component of the stress response system — known as the HPA axis. This network consists of the hypothalamus, the pituitary gland, and the adrenal glands.

The HPA axis relies on a series of hormonal signals to keep the sympathetic nervous system — the “gas pedal” — pressed down. If the brain continues to perceive something as dangerous, the hypothalamus releases corticotropin-releasing hormone (CRH), which travels to the pituitary gland, triggering the release of adrenocorticotropic hormone (ACTH). This hormone travels to the adrenal glands, prompting them to release

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cortisol. The body thus stays revved up and on high alert. When the threat passes, cortisol levels fall. The parasympathetic nervous system — the “brake” — then dampens the stress response.

Techniques to counter stress

The findings of the national survey mentioned earlier support what mental health clinicians experience in their own practices — many people are unable to find a way to put the brakes on stress. Chronic low-level stress keeps the HPA axis activated, much like a motor that is idling too high for too long. After a while, this has an effect on the body that contributes to the health problems associated with chronic stress.

Persistent epinephrine surges can damage blood vessels and arteries, increasing blood pressure and raising risk of heart attacks or strokes. Elevated cortisol levels create physiological changes that help to replenish the body’s energy stores that are depleted during the stress response. But they inadvertently contribute to the buildup of fat tissue and to weight gain. For example, cortisol increases appetite, so that people will want to eat more to obtain extra energy. It also increases storage of unused nutrients as fat.

Fortunately, people can learn techniques to counter the stress response.

Relaxation response. Dr. Herbert Benson, director emeritus of the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, has devoted much of his career to learning how people can counter the stress response by using a combination of approaches that elicit the relaxation response. These include deep abdominal breathing, focus on a soothing word (such as peace or calm), visualization of tranquil scenes, repetitive prayer, yoga, and tai chi.

Most of the research using objective measures to evaluate how effective the relaxation response is at countering stress have been conducted in people with hypertension and other forms of heart disease. Those results suggest the technique may be worth trying — although for most people it is not a cure-all. For example, researchers at Massachusetts General Hospital conducted a double-blind, randomized controlled trial of 122 patients with hypertension, ages 55 and older, in which half were assigned to relaxation response training and the other half to a control group that received information about blood pressure control. After eight weeks, 34 of the people who practiced the relaxation response — a little more than half — had achieved a systolic blood pressure reduction of more than 5 mm Hg, and were therefore eligible for the next phase of the study, in which they could reduce levels of blood pressure medication they were taking. During that second phase, 50% were able to eliminate at least one blood pressure medication — significantly more than in the control group, where only 19% eliminated their medication.

Physical activity. People can use exercise to stifle the buildup of stress in several ways. Exercise, such as taking a brisk walk shortly after feeling stressed, not only deepens breathing but also helps relieve muscle tension. Movement therapies such as yoga, tai chi, and qi gong combine fluid movements with deep breathing and mental focus, all of which can induce calm.

Social support. Confidants, friends, acquaintances, co-workers, relatives, spouses, and companions all provide a life-enhancing social net — and may increase longevity. It’s not clear why, but the buffering theory holds that people who enjoy close relationships with family and friends receive emotional support that indirectly helps to sustain them at times of stress and crisis.

Dusek JA, et al. “Stress Management Versus Lifestyle Modification on Systolic Hypertension and Medication Elimination: A Randomized Trial,” Journal of Alternative and Complementary Medicine (March 2008): Vol. 14, No. 2, pp. 129–38.

Holt-Lunstad J, et al. “Social Relationships and Mortality Risk: A Meta-Analytic Review,” PLoS Medicine (July 27, 2010): Vol. 7, No. 7, electronic publication.

McEwen B, et al. The End of Stress as We Know It (The Dana Press, 2002).

For more references, please see www.health.harvard.edu/mentalextra (/mentalextra).http://www.health.harvard.edu/mentalextra

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Source: https://www.health.harvard.edu/newsletters/Harvard_Mental_Health_Letter/2011/March/understanding- the-stress-response

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