Group on Scientific Research into ME:

Neuroendocrinology of CFS/ME

Dr Anthony CleareReader, 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

nmol

/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 t s

* * *

* * *

* * **

* *

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

050

100150200250300350

-30 -15 0 15 30 45 60 75 90Cor

tisol

cha

nge

from

bas

elin

e (n

mol

/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 60Cor

tisol

cha

nge

from

bas

elin

e (n

mol

/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

hang

e in

fatig

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

0102030405060708090

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 phaseSleepPsychiatric IllnessPast AbuseMedicationStressPhysical ActivityDiet/weight changeOther trait – e.g. geneticUnknown 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