THE PATHOPHYSIOLOGY OF CHRONIC HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
In nature, survival of a species is dependent on the animals quick organization and interpretation of its environment. The brain of the Homo sapien has advanced so much over time that we are the top of the food chain. It is the collective workings of the amygdala, hippocampus and hypothalamus that bring the body information to form perceptions of the outer world and the inner environment of the body for the basic mechanism for survival. When any state of disharmony is perceived, the body begins a stress response as homeostasis is apparently being threatened and therefore quick actions must be taken to adapt. These actions include immediate physiological and behavioral responses such that the organism (you or I) is ready to react to a threat, when this occurs chronically, it becomes a stress. The common mechanism in the different pathways of these actions is hormones and the starting point of this hormone cascade begins in the Paraventricular Nucleus (PVN) of the hypothalamus.
The hypothalamus is activated in the stress response by three main inputs: the suprachiasmatic nucleus (SCN) in response to any dysregulation of the circadian rhythm, cognitive input from the limbic system and the sympathetic portion of the central nervous system. The hypothalamus then releases Corticotropin-releasing Hormone (CRH) which then travels and activates two main hormones in the pituitary gland, which by the way is known as the master gland of the body for it releases all the hormones required to activate the rest of the glands, organs and systems in the body. The anterior portion of the pituitary gland holds six out of eight of the master hormones: Adrenocorticotropic Hormone (ACTH), Thyroid-stimulating Hormone (TSH), Follicle-stimulating Hormone and Luteinizing Hormone (FSH/LH), Growth Hormone (GH) and Prolactin (PRL) while the posterior pituitary holds the other two hormones: Vasopressin (ADH) and Oxytocin.The anterior pituitary gland largely becomes activated once the hypothalamus is activated under stress and releases ACTH into the blood stream while ADH is also releasing from the posterior pituitary.
The Fight-or-Flight Response is the term that is often used to describe the pathway of the HPA axis. This paper will firstly address the release of CRH and its down-wind detriments, specifically focusing on the adrenal glands and then impact of stress on the ovaries. I will then discuss the Ovarian-Adrenal-Thyroid (OAT) axis and how gastrointestinal issues occur due to chronic hyperactivity of The HPA and OAT axis’. A note of the connections of all parts of the system and how dysfunction in certain organs or systems lead to symptoms in other systems will also occur in this paper as no part of the body stands alone and all of it becomes affected under chronic stress.
In referring to diagrams 1 and 2, once the hypothalamus becomes activated in the stress response, CRH is released which travels to and activates the pituitary gland then releasing ACTH and ADH. ACTH is a polypeptide trophic hormone that is released from corticotropes by the cleavage of pro-opiomelanocortin (POMC) and travels through the blood to act peripherally, mostly on the zona fasiciculata of the adrenal cortex. Naturally, ACTH follows the diurnal pattern of cortisol which should be regulated by the natural circadian rhythm of the moon and sun affecting melatonin and sleepiness in the brain. Therefore, naturally and optimally, ACTH should only be released in the morning when we wake with a slight release late afternoon (fig.3). Unfortunately this is not the case as the environment we live in; especially in modern day society which sends our brain stress signals from almost every direction and multiple times per day.
Once ACTH binds to its receptors in the adrenal cortex, it causes P450 enzyme to be cleaved so that glucocorticoids are then synthesized by a process called steroidogenesis while lipoprotein-uptake is simultaneously occurring in the cortical cells so that the bioavailability of cholesterol can be maintained for a long term response. It is thus the response of cholesterol into its different forms of glucocortioids by means of steroidogenesis that causes many of the pathologies resulting from long term activation of the HPA axis.
Cortisol (aka hydrocortisone) is the main glucocorticoid that should come to mind when talking about the adrenal activation response/fight-or-flight/stress response. It is a steroid hormone that is absolutely essential for life as it allows the body to rapidly be ready to react to a stressor by making energy readily available for a reaction. Once released, it immediately acts on the liver to mobilize glucose which increases blood sugar levels. Meanwhile, triglycerides are also being mobilized to maintain a longer term response once glucose reserves are used. Additionally, cortisol tells the body that it does not need to waste any of its spare energy so the immune system(fig.2) becomes suppressed as immunity is low priority in the moments of fight-or-flight and all energy needs to be readily available for use by the skeletal muscles, the heart, lungs and senses (for example your pupils dilate to see farther, your sense of hearing and smell become more acute). Finally in its response, cortisol then causes the enzyme in the adrenal glands to convert epinephrine to norepinephrine which furthers the fight-or-flight response and then cortisol travels back up to the hypothalamus in a negative feedback loop(fig.1) to turn off the release of CRH, telling the hypothalamus, “ok, I’m ready”, which is by definition what the body was trying to do in maintaining/creating homeostasis in the first place!
By now if we could just hypothetically say that that was the end of the story and it was just as simple as the CRH to ACTH to Cortisol release that we were worried about in the stress response, can you see how long term (daily and multiple times per day) activation of this response will long term create pathologies? With Cortisol alone, I see its anabolic behaviour on the liver leading to blood sugar issues then hyperglycemia then diabetes (as we truly aren’t using our muscles to fight or run away and thus the cells of the body just get saturated with sugar and insulin goes haywire). I then predict obesity and a fatty liver would result as triglycerides were also mobilized, muscle and connective tissue would deteriorate, and eventual development of atherosclerosis and cardiovascular disease would occur. Finally, do not forget about the depressed immunity which we all know eventually leads to the big C (ancer). Lastly, the adrenal glands are in overdrive which means eventual adrenal fatigue with a lack of coping to any further stress anyways. That’s just the tip of the ice burg!!!!!Check out the rest of the pathway in figure 4, ACTH does not only cause cortisol to be released from the adrenal glands, aldosterone is also released, and the DHEA pathway is activated which forms the rest of the sex steroids.
Aldosterone is a mineralcorticoid which is secreted from the zona glomerulosa of the adrenal gland and acts on the principle cells of the kidneys which increases blood pressure and changes the acid-base balance in the body. It is released in response to ACTH or in response to the Renal-Angiotensin-Aldosterone (RAA) System. Since I have finally mentioned the kidneys, I am going to remind you that ADH was also released from the pituitary which in its pathway, traveled down to the kidneys to reabsorb water which causes systemic vasoconstriction. Together chronic aldosterone and ADH release eventually lead to hypertension and cardiovascular disease with systemic acid-base imbalances and resulting extra stress on the kidneys. Aldosterone also causes hirsutism in women.
Now let’s get back to fig. 4 and talk about the rest of the adrenal release of the corticosteroids and hypothesize the effects on the gonads!!! Our main form of reproduction (is that not our main purpose in life?) is then altered and often becomes pathological from continual activation of the stress response. For your information, fig. 5 shows the pathway of cholesterol into the sex hormones and so it would seem that activation of the stress response brings about increased levels of androstenedione, testosterone in males and estrone, estradiol, estriol, progesterone and androstenedione in females (the DHEA pathway). This is actually the short term immediate result of stress because the sex hormones then send a negative feedback to the hypothalamus to stop the release of GnRH which in more longer term prevents FSH/LH from being released. Finally, under chronic stress, the adrenals get so fatigued that the DHEA pathway is shunted from (view the dark arrows in figure 4, known as “The Cortisol Shunt”) then we have another issue happening months/years down the line where the push of the sex hormones from the adrenals during the stress response actually depletes and then there is no negative feedback loop to the hypothalamus so the hypothalamus starts increasing its GnRH which increase FSH/LH in the blood and by this time the ovaries and uterus are both very confused (so are the testicles however this paper is to focus on female reproduction). The gonads read all this as massive fluctuations of extra sex hormones being made every time the stress response begins then the suppression of the FSH and LH due to negative feedback which then cause the ovaries to lower their production of estrogen and progesterone. Then in the times where the female might be relaxed for a short period of time, the estrogens and progesterones decrease from the adrenal glands and FSH/LH increase so the ovaries then develop better and start producing more estrogen and progesterone and this is all very confusing for the system as all these four hormones that regulate the female reproductive system are literally all over the map.
The endocrine system of the body along with its release of varying hormones is what controls the menstrual cycle of women and therefore when these hormones deviate from the norm, the female reproductive cycle becomes irregular. Fig. 6 very eloquently shows the connections of the hormones and their actions and you can see that Follic le Stimulating Hormone (FSH) and Luteinizing Hormone (LH) are simultaneously released from the anterior pituitary and work synergistically for the purpose of reproduction. To understand how these hormones would change the female reproductive cycle under chronic stress, let us take the extreme example that a female is so stressed that she is consistently having negative feedback loops occurring back to the hypothalamus so that GnRH is barely released and FSH and LH are very minimal.
FSH is required both in females and males for the maturation of germ cells and thus its deficiency alone can lead infertility. Furthermore the follicle maturing is what causes more estrogen to be secreted from the ovary so with a lack of folliculogenesis the women would then have deficient estrogens (although some are still being released from the adrenals. This gives symptoms such as: changed sex characteristics (loss of breast tissue, increased hair growth, deepening of the voice...) decreased metabolism, osteoporosis, decreased clotting of the blood, worsening lipid profile with an increased risk in cardiovascular disease, sodium and water retention, increased cortisol levels (oh no!!), increased bowel mobility, decreased libido and deterioration of the mental health. Finally, estrogen in very implicated in many forms of cancer, specifically breast cancers.
Deficient LH release means lack of an LH surge and thus no ovulation happens next in the female cycle and since LH matures the oocyte into the secondary oocyte, lack of the LH surge means the ovum may also not mature. Later on in the luteal phase, FSH and LH should work on the ovum to change it into the corpus luteum if fertilization has not occurred ad therefore progesterone starts to be released. Decreased levels of progesterone in the female thenpresents as: increased blood pressure as it is a potent antagonist to aldosterone, increased uterine smooth muscle leading to cramping, bronchoconstriction and thus lung symptoms, systemic inflammation and decreased immunity, unstable mood, finally one of the most presenting symptoms of chronic stress on the female reproductive system is the lack of menstruation as it is due to the combination of progesterone release and estrogen withdrawal that a female sheds her endometrial lining.
Now this hypothetical example is very extreme, it would probably be that the hypothalamus is not under complete suppression by negative feedback and thus there would be some extent of release of both GnRH, thus FSH/LH however any of these symptoms could be appearing. Also recognize that the hypothetical case described above is only occurring until The Cortisol Shunt begins to appear when the adrenals get fatigued and then FSH and LH actually increase allowing for the follicles to perhaps develop properly but now sex hormones are not being released from the adrenals so in the big picture it is still estrogen and progesterone deficiency with a high probability of estrogen dominance. Aside from the symptoms above, FSH and LH are so inherently important to the release of estrogen and progesterone which have huge impacts on the mood and mental health. Thus the stressed out female may come to the clinic for missed periods, more periods or skipped periods, all due to confusing fluctuations of hormones. She may present to the clinic wandering why she is gaining weight while feeling fatigued and slightly depressed with acne sh e has never had before. Ovarian failure and infertility are the largest of threats and are increasingly present in modern society and modern stress.
Now I will introduce another portion of this huge picture: The Ovarian-Adrenal-Thyroid (OAT) axis and how importantly intwined the thyroid gland becomes with the The HPA axis, sometimes known as The HPAG (Hypothalamus-Pituitary-Adrenal-Gonadal) axis(fig 7). Much like the ovaries, the thyroid is also controlled by the endocrine system of the body. Furthermore, it is considered the thermostat of the body, the regulator of metabolic processes and therefore once the stress hormones start to be released, the thyroid gland becomes this mother trying to regulate all the haywire hormones throwing temper tantrums in so many different places of the body. Finally she starts to burn out (become hypothyroid) and this is another big piece of the puzzle. The adrenal, thyroid and gonads are so connected by their hormones that any deficiency or excess in any one organ will surely tax the other two organs and since the adrenals are the huge connection to the HPA axis, when stress is occurring, the adrenals, thyroid and ovaries are all going haywire and becoming fatigued. Too much stress can lead to total failure in any one of these systems and it can become life threatening.
Activation and dysregulation of The HPA axis affects the thyroid in several ways with the most notable being that the secreted levels of T4 and T3 eventually fall while the peripheral conversion of T4 (thyroxine, inactive) to T3 (triiodotyronine, active) is also being largely suppressed by a compromised liver, gut and inflammatory cytokines all which are due to the adrenal release of cortisol. Chronic long-term stress leads to excess T4 (which is still lower than beneficial anyways) which travels in a negative feedback loop to depress the secretion of TSH. There are several methods by which the thyroid invariably becomes affected by the activation of the adrenals however it seems to be the most important effector is the decrease of immunity and increase of inflammation. From this, autoimmune diseases against the thyroid (Hashimoto’s or Grave’s Disease) become a threat, as well as the lack of adequate levels of T3 and TSH as described above. Next, the inflammatory cytokines suppress thyroid receptor site sensitivity so less free T3 is binding and then after that while the adrenals are still pumping out sex hormones, the liver becomes saturated with estrogen and thyroid binding globulin (TBG) is increased so less functional free T3 or T4 levels are traveling around in the blood as they are bound. Nothing happens in the body in a linear fashion, it is all so dynamic and difficult to truly put into words however the patterns that occur specifically with the thyroid during acute stress are often that the thyroid firstly becomes hyperactive and then eventually becomes hypoactive as it can not keep up. The thyroid adrenal axis is imperative to understand as they truly are affect together and need to be treated together. Once the adrenals are activated with ACTH the thyroid is trying to compensate and the ovaries are getting confused. That is probably the best way to describe the OAT axis. Acute symptoms of hyperthyroid then become: weight loss, excess body heat with heat intolerance, the quickening of hair/nail growth, skin becomes moist, palpitations, anxiety and irritability, even psychosis and paranoia can result. In chronic stress however, the female may simply become hypothyroid and present with symptoms such as: low blood pressure, fatigue, dry skin and hair, loss of appetite, slowed digestion, water retention, depressive mood swings, decreased sweating and carpal tunnel syndrome. The thyroid dysfunction then stress the adrenals out even more as the body is feeling more and more overwhelmed, then more cortisol is released again (recall the dysfunctional ovaries also do this) and it all truly becomes a defeating cycle.
As energy and nutrients for the body are being depleted in chronic stress, the Gastrointestinal system is also having trouble so it is absorbing less which means the body becomes truly deficient. The brain-gut axis is another portion of the body that gets very affected under stress as they are connected via sympathetic and parasympathetic nerves(fig.8). Also adrenal and thyroid hormones affect the GI as both the release of ACTH and the decrease of thyroid hormones slow gastric emptying so that the gut becomes sluggish. Cortisol then increases insulin in the blood which decreases absorption of food in the GI and the lower immunity of the body from cortisol creates poor gut flora which means even less T3 is converted. Active thyroid hormone also regulate serotonin which means that the chronically stressed out individual may have intermittent periods of constipation, diarrhea or both. The feasibility of new food sensitivities or allergies and even problems such as Celiac Disease, Chron’s or Ulcerative Collitis can present as autoimmunity can occur in the GI tract as well. We all know that the GI system simply does not work under fight-or-flight more, it must relax to digest and just talking about the GI could be a whole other paper, however the connection to The HPA and OAT axis’ are quickly outlined.
In conclusion, chronic stress can be life threatening. The body compensates in all systems and eventually gets fatigued. Our stress response was meant for our primitive ancestors in which only occasionally they had to run from a predator or fight for their food. We now live in a society where we are go-go-go all day with stress in all forms and all directions. As you have read, there are a plethora of symptoms of chronic stress and presentation in the clinic with hugely vary, one may come in with fatigue, depression and dysmenorrhea while another may come in with palpitations, anxiety, a missed period and alternating diarrhea and constipation. You may decide to call the first presentation PMS syndrome and the second hyperthyroid but is that the true etiology? Think about it. ~Blessings.
References:
Robbins & Cotran Pathologic Basis of Disease. Kumer et al. 2010. Saunders. Ch.24. The Endocrine System. pp.1107-1108.
The Encyclopedia of Natural Medicine. 3rd Ed. Murray et al. 2012. pp. 892.
Guyton & Hall Textbook of Medical Physiology. 2011. Saunders. Ch. 58. The Limbic System and the Hypothalamus. pp. 715-725. Ch. 59. The Autonomic System and the Adrenal Medulla. pp. 729-739.
They Hypothalamic-Pituitary-Adrenal Axis, neuroendocrine factors and stress. C. Tsigos, G. Chrousos. Journal of Psychosomatic Research. Vol 53, Issue 4. pp. 865-871. Oct. 2002.
Chronic Stress Influences the Immune System Through the Thyroid Axis. GA Cremaschi et al. Nov 2000. Life Sci. 67(26): 3171-9.
Figure 1: www.hindawi.com/journals/ecam/2011/950461/fig1/
Figure 2: www.nature.com/nrc/journal/v6/n3/fig_tab/nrcl820_F2.html
Figure 3: www.robbwolf.com/2012/02/23/sleep-sleep-sleep-how-artificial-lighting-and-cortisol-impact-zzzs/
Figure 4: www.youthfulagingcenter.com/adrenal-fatigue.html
Figure 5: http://thatpaleoguy.com/2011/02/14/the-menstrual-cycle-and-exercise-metabolism-part-two/
Figure 7: http://www.drlam.com/articles/ovarian_adrenal_thyroid.asp
Figure 8: http://www.sciencedirect.com/science/article/pii/S0165614704000276
Written by Dr. Ashley Kristina Romanchuk, ND. All Rights to this Information are owned under Mountainash Medicine Corporation, Copyright © in effect