New Advances in the Treatment and Assessment of HPA Axis Dysfunction Q&A
Presenter: Thomas Guilliams, PhD
The relationship between stress and chronic dysfunction has been oversimplified, and often wrongly interpreted, as an adrenal issue. Of course, the adrenal glands are part of the response, but they are rarely the "cause" of the dysfunction.
If the low cortisol is not from 'Adrenal Fatigue' but rather an "adaptive response," how do you adjust that response to start increasing cortisol production again?
DR. GUILLIAMS: The answer depends on what is believed to be the root cause of the low cortisol. For instance, if low morning cortisol (blunted CAR) is due to poor sleep or sleep apnea, then helping the patient sleep or using a device to treat sleep apnea is likely to increase morning cortisol; if low cortisol is due to seasonal affective disorder, access to sunlight/light therapy will likely normalize cortisol. Subjects with PTSD are much more difficult since a strong downregulation has occurred, as are patients with true long-term burnout. These patients will require long-term and careful management of their stressors. My expertise is not in the use of exogenous cortisol (hydrocortisone), but I think this should be used carefully, as it can exacerbate an already downregulated HPA axis.
DR. ZAVA: I agree with all Dr. Guilliams is saying above. If low cortisol is due to lack of cortisol precursors then you might see a response to pregnenolone or progesterone. In testing diurnal cortisol levels in millions of people over the years and looking at what people are doing for hypocortisolism I have seen that progesterone therapy often raises cortisol levels in those with low cortisol more than those with a high level. So part of the issue with these individuals may be low precursor. Same with nutrients such as Vitamin C, pantothenic acid (B5), vitamin A, etc. involved in adrenal synthesis of cortisol. If these are deficient due to diet or whatever, the adrenal glands may just need them to kick-start cortisol synthesis. Most people know when they take these nutrients and get more energy from them.
How would it affect the CAR when waking with an alarm?
DR. GUILLIAMS: This has been looked at in several different studies and while there is some variability in subjects, waking to alarm clock will generally result in a more robust and predictable CAR than spontaneous awakening. This is not to say that waking to an alarm is "better" or "worse" for the HPA axis, though when using waking as a HPA provocation “test” for analytical purposes, waking with an alarm may give the clinician a better assessment of the HPA’s ability to generate a robust CAR. Alarm clocks that slowly increase light (i.e., the Natural Alarm clock) have been shown to create a more robust CAR than those that merely use sound to awaken the subject.
DR. ZAVA: I agree with all Dr. Guilliams is saying. As Dr. Guilliams elaborated so well in his webinar, the correct collection of saliva for evaluating the CAR is very important – start when you first wake up, not when you finally decide to get out of bed. Have your saliva collection tubes close by and organize it all the night before. You only need to collect the equivalent of about 1-2 mL of saliva, and do it in the first five minutes of waking. Also, collect the samples on a typical work day, not a weekend when you have the luxury of sleeping in. ZRT Laboratory is now able to evaluate the CAR by including two extra saliva tubes in the test kit.
Is there a problem if a person doesn't show a rise in cortisol within the first 30 minutes after waking?
DR. GUILLIAMS: Yes. A blunted CAR will result in a more flattened diurnal rhythm overall and is a sign of HPA axis dysfunction. Discovering the root cause of morning hypocortisolism/blunted CAR will be key to helping the patient regain HPA axis function and consequently the chronic management of many systems controlled by the HPA axis. Look for alterations in sleep/circadian rhythm as these will often influence the CAR.
DR. ZAVA: Here it is very important for the patient to include all medications they are taking. A flattened cortisol awakening could be due to overall suppression of cortisol synthesis by synthetic glucocorticoids used for treating inflammatory conditions, including asthma. If you reach for your inhaler after you collect your first sample the second one might be suppressed. The inhaler might contain a synthetic glucocorticoid that suppresses endogenous cortisol synthesis because the brain is registering that the body has adequate glucocorticoids on board. In this case it might not be appropriate to do the CAR test, as it can skew results that would not be appropriately interpreted. I have also frequently seen androgens (mostly DHEA, but also testosterone) cause a transient suppression of cortisol synthesis for several hours. Testosterone inhibits the interaction of Arginine Vasopressin (AVP) with Corticotrophic Releasing Hormone (CRH) in the hypothalamus, which lowers synthesis of ACTH and causes a fall in cortisol. This only lasts several hours and is usually followed by a rebound response and higher cortisol production. So if you are using T or DHEA at night before bed or when you first spring out of bed it might be a good idea to forgo this on the day of saliva testing for CAR, at least for the first hour of saliva collection. It’s possible also that high dose melatonin or other sleeping meds might interfere with the CAR. I have often observed that benzo diazepam-type medications suppress cortisol, but result in a marked rebound and high cortisol level once it wears off, so if you are testing CAR, again, be sure to list all medications, especially hormones and sleep meds.
What is the significance of the ratio between cortisol and DHEA or DHEAS?
DR. GUILLIAMS: If done correctly (molar to molar ratio at the same time point, preferably within the first 30 minutes post waking), the cortisol:DHEA(S) ratio can gauge the relative "age" of the HPA axis. The difficulty is that we need a lab to accurately collect enough samples (collected at the right time) and linked to actual age and other known factors to properly create a set of age-specific reference ranges. Perhaps we can see if ZRT could index a range of salivary cortisol:DHEA-S ratios by age (and sex) and start to see where the trend line would be.
DR. ZAVA: Great idea. Our test reports now have age-related ranges for DHEAS both in saliva and DBS (Dried Blood Spots), and both show progressive tapering with age, as you show in the attached diagram below. We have not looked at salivary or blood cortisol/DHEA-S ratios by age. We have the data in our database and will get that out in a blog soon.
If DHEA is commonly low when cortisol is elevated, when is a good time for a patient to use DHEA supplementation? Is time of day important when considering DHEA supplementation depending on cortisol levels?
DR. GUILLIAMS: As I mentioned, DHEA and DHEA(S) do have a diurnal rhythm which is highest prior to waking, dropping quickly after awakening and continuing to drop the rest of the day. Studies show that this feature is stronger in men than women and in the young vs. old.
DHEA(S) also increases after a stressful event or exercise (following a rise in cortisol). Therefore, DHEA supplementation would seem to be best when done upon awakening or perhaps prior to bedtime to allow for early morning rise; or right after a stressful event/exercise. This, of course, is done in subjects that have been shown to have lower than expected DHEA(S) levels by testing and should not be assumed based on cortisol levels.
DR. ZAVA: From a testing perspective one has to be careful about interpreting DHEA test results as the hormone levels may depend on the body fluid used. How you deliver DHEA (oral, topical, sublingual, and vaginal are the most common routes of administration) may make a big difference in what you see in the body fluid you are measuring it in.
DHEA-Sulfate (DHEA-S) levels increase in saliva, serum, capillary blood, and urine in proportion to the oral DHEA dosage used. When taken orally the DHEA is rapidly converted to DHEA-S in the gut and liver and it shows up in all body fluids above. With oral DHEA therapy, DHEA as well as DHEAS also rise in saliva (DHEA-S is about 100x higher than DHEA in blood, but only about 10x higher than DHEA in saliva due to slower entry of DHEA-S through the salivary gland into saliva). With troche DHEA therapy much of the DHEA enters the bloodstream directly, circumventing the first-pass effect through the gut and liver that converts it to DHEA-S. In this case DHEA-S measurements in saliva may not fully represent the amount of DHEA in the bloodstream, or in saliva. Topical DHEA, which is less commonly used, will increase salivary DHEA levels, but have little effect on DHEA-S levels because the DHEA did not pass through the gut and liver and convert to DHEA-S. ZRT has chosen to measure DHEA-S and not DHEA because DHEA-S is the active hormone, whereas DHEA is a precursor to T. Therefore, we believe that measuring T would be a more accurate assessment of DHEA’s androgenic capacity. Measuring DHEA-S is more reflective of its non-androgenic roles as modulators of the immune system and as a neuroactive steroid that interacts with GABA and dopamine receptors.
How important is it to change adaptogens? Would you suggest to find completely new adaptogens? I am a female who trains 4-5 times a week (weight training mainly), and I am over 40.
DR. GUILLIAMS: There is simply no research to answer this question that I am aware of. There is limited data on how most adaptogens work, and even less comparing and contrasting these botanicals in human outcomes. Probably best to use empirical evidence on how certain adaptogen combinations change your stamina and recovery.
DR. ZAVA: I have seen these adaptogens have significant effects on increasing DHEA-S levels, especially Rhodiola. This is just my anecdotal observation based on looking at reports where people have indicated use of adaptogens, and I agree with Dr. Guilliams that there is, unfortunately, not enough scientific work to explain how these adaptogens work at the cellular/physiological level to enhance DHEA synthesis by the adrenal glands. Much of the good science on Rhodiola has been done in Russia. The cosmonauts used it during long term space flights to increase stamina. I have been very interested in this field of research related to “Mother Nature’s” gifts for our adrenals. I suspect the active components of Rhodiola or other adaptogens affect adrenal DHEA and cortisol synthesis either by direct action of DHEA or cortisol mimicking phytochemicals present in the plants or by activating pathways (e.g., ACTH) or enzymes (e.g., 17, 20 lyase, which converts 17-hydroxy pregnenolone to DHEA) involved in DHEA synthesis (see page 45 of Dr. Guilliam’s book).
Do you find it helpful to also test for cortisone at each collection to frame interpretation of high/low/normal cortisol levels?
DR. GUILLIAMS: There is some evidence that certain individuals may benefit from knowing the cortisol:cortisone ratio (or total), though when this is looked at in saliva, it rarely would change the clinical interpretation. I am an advocate for laboratories to begin looking at this (saliva or urine) and comparing these sorts of data based on metabolic parameters to see if and when this type of information would help the clinician change their recommendation.
DR. ZAVA: I think we are the only laboratory that looks at and plots both urinary free cortisol and cortisone in urine collected four times throughout the day. In most cases cortisol and cortisone parallel each other, meaning the ratio generally stays the same. However, we periodically see patterns that deviate from this. One of these is when someone is using something (hormones, medications, herbs, nutrients) in the morning that affects 11beta hydroxysteroid dehydrogenase type I (converts cortisone to cortisol) or type II (converts cortisol to cortisone). When we see cortisol levels drop rapidly from normal morning values in the second urine void, and then recover, or even rebound to a slightly higher than range value, this usually is associated with some form of hormone therapy. It seems most common with thyroid therapy, but estrogens, progesterone, DHEA, and testosterone can have an effect. This is why it is so important to document what medications are being used – they can have profound, but transient, effects on cortisol levels, and report comments should reflect this apparent anomaly.
It’s also important to have information on both cortisol and cortisone diurnal rhythms when one is high and the other low. Most common is when cortisol is low and cortisone is within normal range or high. Dr. Guilliams does a superb job of explaining this on pages 38 and 39 of his book.
Does cortisol affect the movement of glutamine from muscle tissue to the immune system with intense exercise?
DR. GUILLIAMS: It is well documented that glucocorticoid therapy results in myopathy through a number of mechanisms. Some research suggests that supplemental glutamine, creatine, taurine, and/or DHEA can offset this phenomenon. I am not sure how exercise-induced cortisol production compares with exogenous glucocorticoids in this respect as some (dexamethasone) are much more potent in this regard than others (prednisone). It is also true that elevated cortisol levels mediate some of the post-intense exercise immune suppression. However, I do not know whether glutamine transfer (or its inhibition) has anything to do with these two phenomena.
