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Group on Scientific Research into ME:
Neuroendocrinology of CFS/ME
Dr Anthony Cleare
Reader, Kings College London, Institute of Psychiatry
Background
• Series of studies from our research group into the neuroendocrinology of CFS/ME, beginning in 1994
• Focussing on the role of cortisol, the end product of the hypothalamo-pituitary-adrenal axis
• Original theory came from the known effects of low cortisol in other illnesses, including fatigue
NEGATIVE FEEDBACK
METABOLIC EFFECTS
Questions addressed
• Is cortisol low?
• Is there abnormal control of cortisol?
• Is cortisol related to symptoms?
• When does cortisol change in the natural history of CFS?
• What are the causes of altered cortisol?
1. Is there low cortisol output in CFS?
24 h Urinary Free Cortisol Output
0
20
40
60
80
100
nm
ol/
h/2
4h
'Pure' CFSn=89
CFS + Psychn=32
Controlsn=64
UFC
Cleare et al, Am J Psych, 2001
S a l iv a ry c o rtiso l
0
2
4
6
8
1 0
1 2
1 4
1 6
0 6 0 0 0 9 0 0 1 2 0 0 1 5 0 0 1 8 0 0 2 1 0 0
C lo c k tim e
nmol
/lC o n t ro ls
C F S s u b je c ts
* * *
* * *
* * **
* *
Salivary Cortisol in CFSSalivary Cortisol in CFS
Jerjes et al, 2005
Summary of literature
• Basal Studies Urine – 4/6 low cortisol Serial blood samples – 3/6 low cortisol Serial saliva samples – 2/5 low cortisol
• About 50% studies support low cortisol
Cleare, Endo Rev, 2003
2. Is there an abnormal control of cortisol release?
HPA axis in CFSHPA axis in CFS
0
50
100
150
200
250
300
350
-30 -15 0 15 30 45 60 75 90Co
rtis
ol
chan
ge
fro
m b
asel
ine
(nm
ol/
l)
CFS (n=37)
Controls (n=30)
Cleare et al, J Clin Endocrinol Metab, 2001
CRH Test - cortisol responseCRH Test - cortisol response
-1
0
1
2
3
4
5
0 10 20 30 40 50 60Corti
sol c
hang
e fro
m b
asel
ine
(nm
ol/l)
CFS (n=56)
Controls (n=35)
Roberts et al, Br J Psychiatry, 2004
Salivary cortisol response to Salivary cortisol response to awakeningawakening
Summary of Literature
• Challenge Studies (ACTH and/or cortisol response to a variety of challenges) Overall - 11/16 blunted, none enhanced
Cleare, Endo Rev, 2003
3. Is low cortisol is related to the symptom of fatigue in
CFS?
Randomised, double blind, placebo-controlled trial of a low dose cortisol replacement strategy (hydrocortisone 5-10mg) to raise levels of cortisol
Hydrocortisone therapy in Hydrocortisone therapy in CFSCFS
Effect on fatigueEffect on fatigue
-30
-25
-20
-15
-10
-5
0
baseline 1 month 2 months
% C
han
ge
in f
atig
ue
Placebo-active
Active-placebo
Cleare et al, Lancet, 1999
4. When do patients develop low cortisol levels in the evolution of the illness?
Prospective Cohort Studies Prospective model of a fatigue syndrome
using high risk cohorts – post-viral (EBV infection) and postoperative
naturalistic salivary cortisol profiles. Cohort followed up after EBV infection
No relation of low cortisol to fatigue (acute, 3 and 6 months)
Cohort assessed pre and post major surgery No relation of low cortisol to fatigue (acutely, 3
weeks and 6 months) Low cortisol not a risk factor pre-operatively
Candy et al, Psychol Med, 2003; Rubin et al, Psychosom Med, 2004
Phase of IllnessConclusions
• Acute/sub acute fatigue – No link to cortisol• Early chronic fatigue (6 months) – No link to
cortisol• Late chronic fatigue – Low cortisol
Cortisol does not appear to be a primary cause of fatigue in these cohorts
But – studies are of CF, and too small to exclude a different pattern in tightly defined CFS
5. What causes changes in cortisol levels and regulation?
• Are they a primary feature of the illness or secondary to some of the consequences of being ill with CFS?
• If some HPA axis disturbance is secondary to effects of the illness – e.g. physical inactivity, sleep disturbance, stress levels etc. – then therapy targeting these (e.g. CBT) should reverse the HPA axis changes
CBT in CFS:CBT in CFS:Endocrine EffectsEndocrine Effects
0
10
20
30
40
50
60
70
80
90
Baseline Follow Up
All significant at P<0.05
Daily cortisol output,Daily cortisol output,(saliva) unchallenged(saliva) unchallenged
0
50
100
150
200
250
300
350
Baseline Follow Up
Response to CRH challenge: Cortisol
(a) (b)
Lower cortisol pre-treatment predicted a worse response to CBT
Responders 100 (70) nmol/day Non-responders 70 (44) nmol/day (P<0.05)
(urinary free cortisol)
Cognitive Behavioural Therapy in Cognitive Behavioural Therapy in CFSCFS
ConclusionsConclusions
CBT has biological effects - normalisation of the HPA axis
Most likely exerts HPA axis effects via normalisation of factors mediating HPA axis disturbance such as sleep, deconditioning, inactivity, stress, etc.
Proposed multidimensional model of HPA axis changes in
CFS Illness phase
Sleep
Psychiatric Illness
Past Abuse
Medication
Stress
Physical Activity
Diet/weight change
Other trait – e.g. genetic
Unknown factor(s)
HPA axis change(heterogeneous)
Contributes to fatigue maintenance
Future research
• Aetiological work– Longitudinal, prospective studies– High risk cohorts– Large enough to detect subgroups (if present)– Multidisciplinary – integrative understanding of
different factors
• Treatment studies– Improving therapies and therapy options– Targeting the right patients