Adrenal Gland - the gear box of the car (DHEA and cortisol) – underactive
The adrenal gland is responsible for the body's hormonal response to stress. It produces adrenaline, which stimulates the instant stress hormone response (fight or flight reaction). It also produces cortisol and DHEA, which create the short and long term stress hormone responses. Cortisol suppresses the immune system, breaks down tissues and has a generally catabolic effect. However, these effects are balanced out by DHEA, which has the opposite effect - activating the immune system and building up tissues. All these hormones are made from cholesterol - just one reason why running a low cholesterol is not a good thing!
Both cortisol and DHEA are essential for life - too little cortisol causes the life threatening disease Addison's disease, too much causes the debilitating condition Cushing's syndrome. The name of the game is to get the right balance. To achieve this both hormones must be measured. This can be done with the Adrenal stress profile - salivary (ASP) test. By measuring and supplementing within the physiological range, with biologically identical hormones, one is not going to get any unpleasant side effects, i.e. we are trying to copy Nature and restore normality.
The ASP test looks at cortisol and DHEA levels over 24 hours. This test entails taking salivary samples through the day (yippee, no needles!). Indeed, salivary sampling is felt to be the most accurate way of assessing steroid hormone levels.
An abnormal result may be a symptom of other problems or it may cause problems in its own right. The response of the body to stress (any stress - infectious, nutritional, emotional, physical etc) is to increase the output of stress hormones. This gears the body up for action by raising blood pressure, increasing heart rate, improving mental alertness (which can cause anxiety), increasing energy supply and so on. It is actually metabolically very inefficient because it uses up lots of energy, but totally desirable if one has to fight for one's life! This reaction is essential for short term stress, but unsustainable long term. So time for rest and recovery is equally essential.
Problems arise when the stress is unremitting because eventually the output of the adrenal gland will reduce making one far less able to tolerate stress. Indeed, this is often a complaint of my CFS patients - they simply do not tolerate stress at all well.
The pattern of the result from the adrenal stress test gives some idea where one is along the stress response time line.
Stress responses have been elegantly documented by Hans Selye (Wikipedia:Hans Selye) - indeed he first coined the term "stress".
Interpretation Of The Adrenal Stress Profile Test for DHEA and Cortisol Levels
Levels of DHEA and cortisol vary according to the level of stress and for how long that stress has been applied. Increasing cortisol production is the normal response to short term stress and is highly desirable, so long as the stress is removed and the adrenal glands can recover. On-going, unremitting stress means the adrenal gland and the whole body is in a constant state of alert, does not get time to recover and eventually packs up. So, there are several stages of adrenal function gradually leading to failure:
1. Normal levels of cortisol and DHEA. Normal result. Normal adrenal gland.
2. Raised cortisol, normal DHEA. This indicates a normal short term response to stress. Typically low blood sugar - See Hypoglycaemia - the full story.
3. Raised cortisol and raised DHEA. The adrenal gland is functioning normally but the patient is chronically stressed. So long as the stress is removed, the adrenal gland will recover completely.
4. High levels of cortisol, low levels of DHEA. The body cannot make enough DHEA to balance cortisol. This is the first sign of adrenal exhaustion. This is the first abnormal response to chronic stress. The patient needs a long break from whatever that chronic stress may be - the commonest chronic stress is Hypoglycaemia - the full story, but also consider insomnia, mental, physical or emotional overload or whatever. Pregnenolone can be supplemented to make the patient feel better, but it must be part of a package of recovery, without which worsening can be expected.
5. Cortisol levels low, DHEA levels low. The gland is so exhausted it can't make cortisol or DHEA. By this time patients are usually severely fatigued. Often these is loss of diurnal rhythm so no morning peak. This may also be associated with low melatonin at night.
6. Cortisol levels low, DHEA borderline or normal. This probably represents the gland beginning to recover after a long rest. Pregnenolone may be used to help patients feel better whilst they continue their programme of rest and rehabilitation.
In Addison's disease there is complete failure of the adrenal gland, not because of chronic stress but because of autoimmunity. This is a life threatening disorder and the patient is severely ill. The main clinical symptom is severe postural hypotension and chronic hypoglycaemia. Addison's disease is tested for by a short synacthen test, in which cortisol levels are measured before and after an adrenal gland stimulant ACTH. See (Wikipedia:Addison's disease)
Many patients with CFS are given this test, which is found to be normal resulting in the patient being told their adrenal gland is fine and no action is required. The problem with this test is it only shows where the adrenal gland is completely non-functioning, it does not diagnose partial adrenal failure or adrenal stress and no measurements of DHEA are made. This makes it potentially misleading.
I used to treat DHEA deficiency with DHEA. However I believe pregnenolone is more physiological because it is upstream of all adrenal hormones including progesterone and cortisol.
Cholesterol is the raw material from which steroid hormones are made in the body. The next biochemical step is pregnenolone- this is the mother and grandmother of all steroid hormones. Starting off with pregnenolone means that all steroid hormones can be naturally synthesised in the correct physiological balance.
In theory this should greatly simplify the business of prescribing and monitoring hormones because the body can do its own natural balancing act. Please see Wikipedia entry on Pregnenolone
A physiological dose is pregnenolone 50mgs. It is better absorbed under the tongue. This works because sublingual doses bypass the liver - the so-called "first pass effect".
This advice applies equally to men as it does to women. If you are taking DHEA now or if a future Adrenal Stress Profile (ASP) result shows low levels of DHEA, my advice is that you should consider taking/swapping to pregnenolone. If you do the ASP test through my practice, then I will recommend pregnenolone if indicated by the results. In addition to CFS sufferers, post menopausal women and those aged over 50 may also benefit from this therapy. For those 'transferring' from DHEA to pregnenolone, the conversion rate is approximately 1:2, so that if you are currently taking 25 mg daily of DHEA then you should transfer to 50 mg daily of pregnenolone.
DHEA is easy. Low levels mean a deficiency and supplementation with pregnenolone is indicated. Sometimes I see a raised DHEA. This can occur in polycystic ovary disease in women and if there were symptoms suggestive of this (irregular periods, lower abdominal pain, infertility) then an ultrasound scan of the pelvis is indicated. High DHEA is a stress response and the causes of such needs looking for. I suspect the most common cause is metabolic syndrome and hypoglycaemia.
Cortisol is more awkward. Levels vary according to the short term level of stress and for how long that stress has been applied. Increasing cortisol production is the normal response to short term stress and is highly desirable, so long as the stress is removed and the adrenal glands can recover. On-going, unremitting stress means the adrenal gland and the whole body is in a constant state of alert, does not get time to recover and eventually packs up. Pregnenolone is upstream of cortisol so taking this should support cortisol production
Prescribing hydrocortisone for CFS
In patients in which the ASP shows a deficiency of cortisol, it is worth trying hydrocortisone. This is the biologically identical hormone and if given in small doses (5-10mgs in the morning) has no side effects and no suppression of the adrenal gland. There is no need to carry a steroid card, no long term side effects and no need to tail the dose off once stopped. I see hydrocortisone as a crutch to the adrenal gland - it allows it to rest as little before resuming normal production after several months or years once the sufferer is considerably better. There is no need to recheck levels of cortisol once on treatment.
It may be that pregnenolone will be more effective as cortisol replacement - time will tell - watch this space!
A New Hydrocortisone Trial
Another randomised, controlled, crossover trial of low-dose hydrocortisone treatment for CFS has recently been published. 32 participants, fulfilling both the Oxford and CDC 1994 criteria, completed this short-term trial. Participants received 5mg or 10mg of hydrocortisone for 28 days and placebo for 28 days.
The results revealed modest, statistically significant improvements in fatigue with this low-dose hydrocortisone treatment compared with placebo. The degree of disability was also reduced with hydrocortisone treatment but not with placebo. There was no significant difference in changes in fatigue score when 5mg and 10mg doses were compared. The authors suggest that, in view of the lack of dose response in this study, 5mg is a sufficient low dose of hydrocortisone.
Participants who responded to this hydrocortisone treatment did not differ from "non-responders" in terms of their pre-treatment cortisol levels. Although none of the participants in this study had a current psychiatric illness, those who responded to hydrocortisone treatment had fewer psychiatric symptoms prior to treatment.
Based on the results of the insulin stress test, this short-term, low dose hydrocortisone treatment was not found to cause significant suppression of adrenal gland function. None of the participants dropped out of the study and only minor side effects were reported.
The authors conclude that this low-dose hydrocortisone treatment resulted in "significant reduction in self-rated fatigue and disability in patients with chronic fatigue syndrome".
This study sheds interesting light on the possible role of low cortisol levels in the disease processes involved in CFS. Caution is required, however, in interpreting the results. Participants' baseline cortisol levels could not predict their response to hydrocortisone treatment and participants appeared to have baseline cortisol levels within the normal reference range.
In another randomised controlled trial of hydrocortisone therapy ( see Interaction 29, page 21 for a review), McKenzie at al., used a higher "low-dose" hydrocortisone treatment of 25 - 35mg daily. They found that this dose was associated with some improvements in symptoms but caused significant adrenal suppression. Neither of these research teams currently recommended the use of hydrocortone as a treatment for CFS. The present study assessed the effects of hydrocortisone treatment in the short-term only. As the authors point out, further studies, involving longer durations of treatment and follow-up are required to assess the long-term effectiveness and safety of this treatment.
Reference: Cleare et al; The Lancet, 1999, Vol. 353 February 6, p455-458
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