Hypothalamic Pituitary Adrenal Axis (Dysfunction)

<p>From: <a href="https://www.hindawi.com/journals/isrn/2013/784520/">A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome</a></p>

<p>Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been found in a high proportion of chronic fatigue syndrome (CFS) patients and includes enhanced corticosteroid-induced negative feedback, basal hypocortisolism, attenuated diurnal variation, and a reduced responsivity to challenge. A putative causal role for genetic profile, childhood trauma, and oxidative stress has been considered. In addition, the impact of gender is demonstrated by the increased frequency of HPA axis dysregulation in females. Despite the temporal relationship, it is not yet established whether the endocrine dysregulation is causal, consequent, or an epiphenomenon of the disorder. Nonetheless, given the interindividual variation in the effectiveness of existing biological and psychological treatments, the need for novel treatment strategies such as those which target the HPA axis is clear.</p>

<p>From: <a href="https://www.nature.com/articles/nrendo.2011.153">Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome | Nature Reviews Endocrinology</a></p>

<p>The weight of current evidence supports the presence of the following factors related to hypothalamic–pituitary–adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS): mild hypocortisolism; attenuated diurnal variation of cortisol; enhanced negative feedback to the HPA axis; and blunted HPA axis responsiveness.</p>

<p>From: 'The Role of Adrenal Dysfunction in Chronic Fatigue Syndrome' <a href="https://www.holtorfmed.com/adrenal-dysfunction-and-chronic-fatigue-syndrome/">https://www.holtorfmed.com/adrenal-dysfunction-and-chronic-fatigue-syndrome/</a></p>

<p>While CFS and <a href="https://www.holtorfmed.com/adrenal-fatigue/">adrenal fatigue</a> are not the same, adrenal function may play a role in it. Those with CFS are often found to produce a low amount of the hormone cortisol, which is produced by the <a href="https://www.holtorfmed.com/functions-and-purpose-of-adrenal-glands/">adrenal glands</a>. Furthermore, CFS is a malfunction of the pituitary, a pea-sized gland at the base of the skull, which regulates all our hormones. The pituitary, hypothalamus and adrenals all work together as part of the HPA axis to regulate our health and hormones. Analysis of the data in over 50 studies that assessed adrenal function in CFS and fibromyalgia patients demonstrates that the majority of these patients have abnormal adrenal function due to hypothalamic-pituitary dysfunction.</p>

<p>Deficiencies in <a href="https://www.holtorfmed.com/index.php?section=downloads&file_id=37" target="_blank">hormones</a> like cortisol, DHEA, aldosterone, pregnenolone, estradiol, progesterone, testosterone and growth hormone are often missed or poorly treated because doctors have come to rely on standard blood tests that require an intact pituitary and hypothalamus for diagnosis and dosing of hormone levels. There is, however, severe hypothalamic and pituitary dysfunction with CFS, making the standard blood tests inadequate. Evaluating hormone function, not just hormone levels, can help diagnose CFS and adrenal fatigue; and when properly treated and balanced, tremendous results can be achieved.</p>

<p>Although a concept that is sometimes uncomfortable and foreign to traditional medical styles of thinking, the need for multiple interventions is required for effective treatment of such complex illnesses like CFS and adrenal fatigue. The HPA axis works as the body’s energy and hormone regulator. An imbalance between any part of the axis can affect the entire body system and treatment for such disorders requires a well-rounded approach to restore function. Therefore, adrenal and pituitary dysfunction often require treatment with several hormones. When treatment is received, individuals with devastating syndromes like CFS, adrenal fatigue and fibromylagia can “get their lives back” despite the fact that they were previously told, “there is nothing that can be done.”
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From: 
The top of the HPA axis chain - the hypothalamus - is part of the limbic system in the lower brain. It links the nervous and endocrine systems together via the pituitary gland. (The hypothalamus also regulates our circadian rhythms (and thus sleep) and the autonomic nervous system.

ADH (vasopressin) is produced in the hypothalamus and then carried into the blood via the pituitary gland. Aldosterone is produced by the adrenal glands in response to angiotensin II, ACTH, potassium or via messages from the stretch receptors in the heart that blood pressure has fallen.
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<p>From: 'Chronic Fatigue Syndrome and Stress: A New Frontier for Treatment?' https://chriskresser.com/chronic-fatigue-syndrome-and-stress-a-new-frontier-for-treatment/</p>

<h3 dir="ltr">Chronic Fatigue Syndrome and the Hypothalamic-Adrenal-Pituitary Axis</h3>

<p dir="ltr">The HPA axis is the body’s control center for reactions to stress, and in turn regulates many other body functions like digestion and immunity. When we interact with a stressor, the body releases a cascade of hormones which eventually reach the adrenals and stimulate the production of other hormones like cortisol (the main stress hormone), dehydroepiandrosterone (DHEA), and aldosterone. These hormones work to keep blood sugar elevated and helps the body retain sodium and fluid so that blood pressure stays high and blood sugar levels can keep up with the fuel demands of the brain and other vital organs during times of stress. This process is important in maintaining life in a true “fight or flight” response, but in the modern world we constantly activate the HPA axis for small stressors like traffic or missing our train. With constant activation, the adrenals can become “worn-out”. Someone with hypoadrenalism will experience fatigue, depression, and low cortisol levels – all markers that are similarly found in chronic fatigue syndrome.
HPA axis dysfunction is not currently evaluated in potential chronic fatigue syndrome patients as part of the diagnostic process, as evidenced by the CDC criteria listed above. However, looking at recent research, it is clear that HPA axis function is an important part of the symptoms experienced by CFS patients.
Hypoadrenalism (low or “worn out” adrenals) in its most severe state presents as Addison’s disease, which in industrialized nations is most commonly caused by an autoimmune attack of the adrenal glands. In Addison’s disease, some or all of the adrenal hormones are not produced in sufficient amounts, which as you can imagine, causes many problems including fatigue, anorexia and/or weight loss, nausea/vomiting, hypotension and/or postural hypotension, muscle and joint pain, salt cravings, sexual dysfunction, and psychiatric symptoms.(<a href="http://www.uptodate.com/contents/clinical-manifestations-of-adrenal-insufficiency-in-adults?source=search_result&search=adrenal+insufficiency&selectedTitle=1%7E150">4</a>) Chronic Fatigue Syndrome and Addison’s disease have many overlapping symptoms, the most important of which is fatigue.
Both Addison’s disease patients and CFS patients show low cortisol output. Morning cortisol levels measured in the saliva have been shown to be low in CFS patients (<a href="http://journals.cambridge.org/production/action/cjoGetFulltext?fulltextid=5946440">5</a>), and 24-hour urinary free cortisol is also lower in CFS patients than controls. (<a href="http://ajp.psychiatryonline.org/article.aspx?articleID=174711">6</a>) CFS patients are likely to have undergone early trauma (<a href="http://archpsyc.ama-assn.org/cgi/reprint/63/11/1258.pdf">7</a>), which, even in healthy adults, is associated with lowered HPA axis reactivity. (<a href="http://www.sciencedirect.com/science/article/pii/S0278584609001250">8</a>, <a href="http://www.sciencedirect.com/science/article/pii/S0006322307004313">9</a>) The lowered HPA axis reactivity often found in CFS patients with history of trauma is associated with having increasing symptoms compared to CFS patients without a history of trauma. (<a href="http://www.sciencedirect.com/science/article/pii/S0022395613000447">10</a>)
Despite this research, it’s still not clear whether HPA axis dysfunction is a cause of CFS or if it comes as result of the condition. Nonetheless, it has been proposed that HPA axis dysfunction in CFS is a vicious cycle, meaning HPA axis dysfunction may be involved in the genesis of CFS, but it also propagates ongoing symptoms once the syndrome manifests. (<a href="http://www.sciencedirect.com/science/article/pii/S1043276003002649">11</a>)
Whether HPA axis dysfunction is the chicken or the egg in CFS may be determined by future research, but for those of us trying to deal with it today, it’s important to determine whether normalization of the HPA axis improves symptoms. Treatment with replacement doses of hydrocortisone have been shown to be helpful but at the expense of adrenal suppression, (<a href="http://jama.ama-assn.org/content/280/12/1061.short">12</a>) while treatment with low dose hydrocortisone (5 or 10 mg daily) was shown to be effective without associated adrenal suppression. (<a href="http://jama.ama-assn.org/content/280/12/1061.short">13</a>) Another study showed that symptom responders to low dose hydrocortisone (those whose fatigue levels were reduced) showed significant increases in cortisol to human CRH, which reversed the previously observed blunted response compared to non-responders. (<a href="http://jcem.endojournals.org/content/86/8/3545.short">14</a>) Though there are limited studies on hydrocortisone treatment of CFS, these studies show that improving cortisol levels is likely important in reducing symptoms.</p>

<h3 dir="ltr">Improving HPA Axis Activity Naturally</h3>

<p dir="ltr">Because there seems to be a connection between HPA axis functioning and CFS symptoms, it is important to make sure that your adrenals are working their best. Pay special attention to the lifestyle factors like sleep and stress reduction with mind-body activities for the best results. These are perhaps the most important (and most overlooked) factors for recovery of adrenal function and improvement of CFS symptoms.</p>

<h4 dir="ltr">Adrenal Testing</h4>

<p dir="ltr">If you have been diagnosed with CFS and don’t know how your adrenals are functioning, it’s an excellent idea to do a salivary adrenal panel which will measure your cortisol output over four different intervals during the day. This is different from having your cortisol level tested at the doctor’s office, as that is a one-time test and doesn’t give you the picture of what the adrenals are doing the whole day. In some states, you can order your own test kit from <a href="https://directlabs.com/OrderTests/tabid/55/language/en-US/Default.aspx">directlabs.com</a>. Otherwise, you’ll have to have your healthcare practitioner order one for you.</p>

<p dir="ltr">A healthy whole foods diet that minimizes food toxins and emphasizes nutrient dense foods (such as the Paleo diet) is an excellent start. A diet like this will be high in many of the nutrients important for the CFS patient which help the HPA axis function including Vitamin C (<a href="http://informahealthcare.com/doi/abs/10.1081/ERC-200044126">15</a>,<a href="http://ajcn.nutrition.org/content/86/1/145.short">16</a>,<a href="http://europepmc.org/abstract/MED/7772741">17</a>) magnesium, (<a href="http://europepmc.org/abstract/MED/10761188">18</a>,<a href="http://www.sciencedirect.com/science/article/pii/S0306987709007300">19</a>,<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/pmc1855626/">20</a>) pantothenic acid, (<a href="http://jn.nutrition.org/content/54/3/403.short">21</a>) and pyridoxine (<a href="http://endo.endojournals.org/content/67/1/97.short">22</a>).
Patients with CFS who are on a Paleo diet may want to consider increasing their sodium intake. It can sometimes be difficult to consume a lot of sodium, and those with CFS and/or hypoadrenalism should be sure to get a fair amount of it so as to minimize the symptoms of low blood pressure. If low blood pressure is a concern it may also be a good idea to supplement with licorice root which potentiates the action of cortisol. (<a href="http://www.imjournal.com/resources/web_pdfs/popular/1008_anderson.pdf">23</a>) Note that licorice root supplementation is contraindicated if you have high blood pressure.
You’ll also want to consume foods (or supplements) with probiotic bacteria, such as kombucha, kefir, yogurt, and sauerkraut. It has recently been shown that the gut flora of rats has an effect on the HPA axis. Rats that had no exposure to microorganisms (germfree; GF) had significantly higher ACTH and corticosterone responses to restraint stress than did rats with normal gut bacteria. (<a href="http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2004.063388/full">24</a>) Another study in rats showed that those exposed to endotoxin (like that which a human would be exposed to if they acquired a pathogen) displayed altered HPA axis activity. (<a href="http://www.pnas.org/content/97/10/5645.short">25</a>) Stress is known to alter the gut microbiota, and in turn this change alters the HPA axis. (<a href="http://www.sciencedirect.com/science/article/pii/S0166223613000088">26</a>) It seems that normal gut flora is required for proper HPA axis activity and that clearing of pathogens and replacing lost beneficial bacteria with probiotic supplementation will likely benefit those suffering from HPA axis dysfunction.</p>

<h4 dir="ltr">Mind-Body Medicine</h4>

<p dir="ltr">It has been shown that those of us who are highly neurotic and who experience depression and self-consciousness have blunted responses to stress tests. (<a href="http://www.nature.com/npp/journal/v31/n7/abs/1301012a.html">19</a>) When we work to change these thoughts and behaviors, we can start to re-train the HPA axis and feel better. Mind-body medicine techniques can help to re-train the HPA axis. Yoga, in particular, can help to reduce anxiety, depression, and perceived stress. (<a href="http://ict.sagepub.com/content/8/1/37.short">20</a>) In a study on mindfulness-based stress reduction, 40% of participants had abnormal cortisol secretion patterns before the intervention and afterwards there was a change to a more normal cortisol rhythm. (<a href="http://www.sciencedirect.com/science/article/pii/S0306453003000544">21</a>) The important thing is to find a mind-body medicine technique that you enjoy and will do on a regular basis. The more consistently you practice, the more benefits you’ll receive. Some examples include tai chi, meditation, deep breathing, biofeedback, the Feldenkrais method and more! Try them all and find out which one you like best.</p>

<h4 dir="ltr">Sleep</h4>

<p dir="ltr">If you have chronic fatigue syndrome, don’t overlook sleep! Sleep deprivation and disordered sleeping cause HPA axis hyperactivity, (<a href="http://www.hindawi.com/journals/ije/2010/759234/abs/">22</a>) so make sure to get to get at least 7-9 hours nightly, and try to go to bed at the same time each night. Chris has some great tips about sleep in his upcoming book, <a class="easyazon-link" href="https://www.amazon.com/Your-Personal-Paleo-Code-Reverse/dp/031632289X" data-cart="n" data-cloak="n" data-identifier="031632289X" data-locale="us" data-localize="n" data-popups="n">Your Personal Paleo Code</a>(published in paperback as <em>The Paleo Cure</em> in December 2014), so be sure to check that out! You can also read more about better sleep on this site <a href="http://chriskresser.com/why-most-people-are-sleep-deprived-and-what-to-do-about-it">here</a>.</p>

<h4 dir="ltr">Time Management</h4>

<p dir="ltr">Another successful strategy that helps a lot of my patients is practicing time management skills. A lot of us tend to run around like chickens with our heads cut off, trying to do everything at once but actually accomplishing very little. With proper time management, you can find time to fit in proper sleep, mind-body medicine, and make delicious, healthy meals and you’ll probably find that you get <em>more</em> done in <em>less</em> time. Check out both of Chris’ podcasts about time management <a href="http://chriskresser.com/how-to-be-insanely-productive-without-destroying-your-health">here</a> and <a href="http://chriskresser.com/how-to-be-insanely-productive-without-destroying-your-health-2">here</a>for more information. When we know exactly what we should be doing at any given moment, we spend a lot less time procrastinating. Plus, when we’re getting things done our stress level goes way down, helping the HPA axis to function more appropriately.</p>

Hypothalamic Pituitary Adrenal Axis (Dysfunction)

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