Treatment with bioidentical cortisol: research

[Guest guest]

http://www.endfatigue.com/book_notes/Fftf_chapter_4.htmlTreatment of Hypothalamic-Pituitary-Adrenal Axis Dysfunction in

Patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)Points addressed:

• A review of the literature regarding evidence of significant

hypothalamic-pituitary-adrenal axis (HPA) dysfunction in CFS and FM. • Indications and efficacy of treatment with physiological doses of cortisol • Expected risks and benefits of such treatmentAbstract:There

is clear evidence that adrenal axis dysfunction is present in patients

with chronic fatigue syndrome (CFS) and fibromyalgia (FM) 1-21,23-28 and that treatment with low physiologic doses of cortisol have been shown to be safe, appropriate and effective.8,9,10,23,30

It should be considered the standard of care to treat patients with CFS

and FM who have baseline cortisol levels under 12 ug/ml.8,9,10,31,32,33 Evidence for significant HPA axis dysfunction with resultant adrenocortical dysfunction:A study published in the ls New York Academy of Sciences entitled Evidence

for and Pathophysiologic Implications of Hypothalamic-Pituitary-Adrenal

Axis Dysregulation in Fibromyalgia and Chronic Fatigue Syndrome discussed the evidence for HPA axis insufficiency in CFS and FM. They conclude, "Our

group has established the impaired activation of the

hypothalamic-pituitary-adrenal axis is an essential neuroendocrine

feature of this condition." 27Cleare et al published a study in the American Journal of Psychiatry

that obtained 24-hour urine collections from 121 consecutive patients

with CFS. They found low 24 hour cortisol levels in all of the CFS

patients. The authors conclude, "Urinary free cortisol was

significantly lower in the subjects with chronic fatigue syndrome

regardless of the presence or absence of current or past comorbid

psychiatric illness…From whatever cause, low circulating cortisol is

associated with fatigue; furthermore, raising cortisol levels can

reduce fatigue in chronic fatigue syndrome. Thus, this study provides

further evidence that adrenocortical dysfunction in chronic fatigue

syndrome, whatever the etiology and whether primary or secondary, may

be one piece of the multifactorial jigsaw underlying the production of

symptoms in chronic fatigue syndrome." 7 The

authors agree that treating this adrenocortical dysfunction with

cortisol replacement is a fundamentally necessary part of the

appropriate multi-system treatment of this condition. Another study published in the Journal of Endocrinological Investigation performed a combination of stimulation tests on FM patients. They found over 95% of these patients had HPA axis dysfunction.3 They state, "The

etiology and pathophysiology of this disease is not fully understood

but the current data suggests that the PFS [Primary Fibromyalgia

Syndrome] is not a primary disease of muscle. In contrast, an

increasing amount of evidence suggests that the central stress axis,

the HPA axis, seems to play an important role in the development of

PFS…This study clearly shows that the HPA axis is underactivated in

PFS..." 3Trophy et al. administered

interleukin-6 (IL-6), which is a potent stimulator of the HPA axis, and

measured plasma ACTH and cortisol levels. They found a delayed ACTH

response in these patients, a state that is consistent with a defect in

the hypothalamic CRH neuronal function, as an etiology of symptoms in

these patients.2Cortisol levels normally increase

with pain, but it has been shown that patients with CFS and FM either

cannot appropriately increase cortisol production with pain or the

inability to increase cortisol causes the increased pain. A study

published in the November 2005 Journal Arthritis and Rheumatism demonstrated

this strong relationship between cortisol levels and pain in

individuals with CFS and FM and that low cortisol levels alone

explained 38% of the variation in pain upon waking. The authors

conclude, "The results of this study indicate that pain symp­toms

in women with FM are associated with cortisol concentrations during the

early part of the day…These data support the hypothesis that HPA axis

function is associated with symptoms in FM and accounts for the

substantial percentage of pain symptom variance during the early part

of the day." 28A study published in the Brazilian Journal of Infectious Disease

(figure 2) demonstrates that in this type of patient population a

baseline cortisol level of less than 12 has a specificity of greater

than 90% for adrenocortical dysfunction and a level less than 10 ug/dl

has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study as well as by others is 12 ug/dl.31,33

In addition, a normal ACTH does not rule-out secondary hypoadrenalism,

but an abnormally low or low normal ACTH level can be considered

confirmatory.Dynamic testing: Dynamic

testing is certainly useful in straight forward primary and secondary

adrenal insufficiency, but in patients with CFS, there is a complex

interaction of hypothalamic and pituitary dysfunction. This results in

a complex response that is initially elevated and then blunted,

resulting in what is thought to be conflicting results, depending on

which stimulation test was used, how an abnormal is defined and whether

or not ACTH/cortisol ratios were used. 1,3,8,9,19,34-39

Consequently, the standard criteria does not apply to these patients

significantly reducing the usefulness of dynamic testing with CFS and

FM.1,9,19,27,34-39 It has been shown that a single

ACTH stimulation test misses the majority of FM/CFS patients that have

adrenocortical deficiency, but when a combination of stimulation tests

are used, such as metyrapone test, or more sophisticated analysis is

used, close to 100% of these individuals have documented adrenocortical

dysfunction.1,3,8,9,19,27,34-39 Numerous studies

demonstrate that this lack of sensitivity likely explains the seemingly

contradictory findings between studies using stimulation tests.1,3,8,9,19,27,34-40 For instance, et al in Clinical Endocrinology

did 1ug ACTH stimulation tests on subjects with CFS and found a

significant decrease in the delta cortisol value of patients with CFS

vs. normals, but found that the reliance on this test and the arbitrary

cutoffs that apply significantly impacts the sensitivity of stimulation

tests in the patient population. They conclude, "In conclusion, the

amount of cortisol released following stimulation with 1ug ACTH, is

lower in CFS patients than in healthy volunteers…We propose, as has

been suggested from previous studies, that the abnormality of HPA

regulation is more likely to be central in origin. The demonstration of

low basal ACTH in our CFS cohort [as in this case] would have supported

this view…There is considerable debate surrounding the optimal dose of

ACTH to use, with concern that the 250 mcg dose is "superphysiologic'

and may produce cortisol responses in patients suspected of having

pituitary adrenal insufficiency that are falsely

reassuring...Disparities between our healthy volunteer data and those

of other groups using the 1 microgram ACTH test suggest that the test

may not be as reliable as previously indicated…replacement therapy may

more appropriately involve not only glucocorticoid, but

mineralcorticoid supplements also." 19Another

study that clearly demonstrates this confusion and that standard

stimulation tests are not a reasonable method of evaluation of

adrenal-cortical dysfunction is published in the Journal of Clinical Endocrinology and Metabolism entitled Evidence for Impaired Activation of the Hypothalamic Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome.

The study found that compared to normal individuals, CFS patients were

shown to have significantly reduced basal glucocorticoid levels

(average 89 vs 148 nmol/l) and a low 24 hour urinary free cortisol

excretion (122.7 nmol/L vs 203 nmol/L). The level of cortisol binding

globulin CBG was also significantly higher in CFS patients making the

free cortisol index lower in the patients (2.9 vs 8.9). There was a

significant attenuated net integrated ACTH response to CRH but there

was an initial increased initial sensitivity to ACTH with a reduced

maximal response.1 Although

this cortisol response to ACTH is clearly abnormal for all of the

patients with CFS, the dose response curve varies. There is an initial

exaggerated response followed by an abnormally blunted response, which

is not the case for patients with primary or secondary adrenocortical

insufficiency without a dysfunctional hypothalamus. Consequently,

standard dynamic testing is not medically useful in these patients and

it is improper to use the defined normal cutoffs of response as is done

with other conditions. This has been demonstrated in other studies as

well.1,3,8,9,19,27,34-39Kirnap et al in a study published in Clinical Endocrinology

compared standard and low dose ACTH stimulation tests on patients with

primary fibromyalgia syndrome (PFS). They found a significantly reduced

peak cortisol response in the PFS verses controls. They also found that

if the standard cutoff of 550 nmol/l was used with the standard ACTH

stimulation, many of the patients would have misdiagnoses as normal.4 There

are a number of theories that have been postulated to explain such a

response. The author of this study postulates that this is due to a

lack of CRH (corticotrophin releasing hormone) with a secondary

hyperresponsivness from inadequate levels of ACTH. They alternatively

state that this HPA axis defect could be secondary to a chronic viral

infection. Treatment:Further supporting

the use of low dose cortisol in these patients is the fact that such

treatment has been shown to improve the HPA axis response in these

patients. This is counterintuitive to what physicians are taught and

have found with higher pharmacological doses of glucocorticoids. In a

study published in the 2001 Journal of Clinical Endocrinology & Metabolism entitled Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy,

the authors utilized ACTH and cortisol responses to CRH, insulin stress

test, D-fenfluramine and 24 hour urinary free cortisol in 37 patients

with CFS and treated these patients with low dose cortisol. They found

that the treatment resulted in significant improvement and not only was

there no adrenal suppression, but rather there was an improvement in

the HPA axis as documented with CRH testing. They concluded, "In

this group, there was a significant increase in the cortisol re­sponse

to human CRH, which reversed the previously ob­served blunted responses

seen in these patients. We conclude that the improvement in fatigue

seen in some patients with chronic fatigue syndrome during

hydrocortisone (same as cortisol) treatment is accompanied by a

reversal of the blunted cortisol responses to human CRH." 8In a randomized, double-blind, placebo controlled, crossover, intent to treat trial published in The Lancet, patients

with chronic fatigue syndrome were treated with low dose hydrocortisone

(5-10 mg/day) or placebo. The study found significant improvements in

those treated with low dose hydrocortisone vs. placebo and 28% improved

to normal levels. The authors concluded, "This study shows that

low-dose hydrocortisone results in significant reduction in self-rated

fatigue and disability in patients with chronic fatigue syndrome…The

degree of disability was reduced with hydrocortisone treatment, but not

with placebo. Insulin stress tests showed that endogenous adrenal

function was not suppressed by hydrocortisone." 9 This demonstrates the effectiveness and appropriateness of this treatment. Another

randomized control trial published in JAMA also found significant

improvement in fatigue scores with hydrocortisone replacement, but they

used excessive dosing of 25-35 mg of cortisol. It is recommended that

dosing be limited to 10-20 mg/day, as these doses have been shown to

not be associated with any untoward effects and carries little to no

risk of adrenal suppression.10,23,30,31 This considerable safety and negligible risk is also confirmed in endocrinology texts.54Bashetti has published a number of studies on cortisol and CFS. He writes in the Journal of Endocrinology and Metabolism, "Hydrocortisone, the glucocorticoid that is routinely prescribed to correct the chronic cortisol deficiency of patients with 's disease, has recently been confirmed to be significantly effective also in the treatment of chronic fatigue syndrome (CFS). This comes as no surprise if we consider that CFS and 's disease share 26 features." 41A randomized, double blind placebo-controlled, intent to treat study by Teitelbaum published in the Journal of Chronic Fatigue Syndrome documented

the effectiveness of an integrative treatment approach to CFS and FM

that includes low dose cortisol (7.5-20 mg/day). The authors conclude,"

Significantly greater benefits were seen in the active group than in

the placebo group for all primary outcomes. Using an integrated

treatment approach, effective treatment is now available for FMS/CFS." 31A subsequent editorial in the peer reviewed, Journal of the American Academy of Pain Management

reviewed this study and agreed that an integrative approach that

includes low dose cortisol is the standard of care for these

conditions. The author states, "The study by Dr. Teitelbaum et al.

and years of clinical experience makes this approach an excellent and

powerfully effective part of the standard of practice for treatment of

people who suffer from FMS and MPS [myofacial pain syndrome]— both of

which are common and devastating syndrome." 48 The

consensus opinion among those who are experts in the treatment of CSF

and FM is that a treatment approach that includes low-dose cortisol is

the standard of care. A subsequent commentary by Teitelbaum published in JAMA states, "Our

previously published pilot study and the work of Jefferies suggests

that using low-dose hydrocortisone in CFS as dosages of 7.5 mg to 20

mg/day is safe and effective. These low dosages have not caused adrenal

suppression…We recently completed a randomized, double-blind study that

tested the effectiveness of treating patients with fibromyalgia and CFS

for hypothalamic dysfunction in an integrated manner. This included

treating suspected hormonal deficiencies (including low hydrocortisone)

and the sleep disorder simultaneously. Using this protocol in 72

patients resulted in a significant improvement in active vs. placebo

group." 42 Cortisol replacement appears to be an

essential part of a comprehensive treatment approach that can be used

successfully in the treatment of CFS and FM.31,42 A

study published in JAMA found that nearly half of the patients treated

with mineralcorticoid reported complete or nearly complete resolution

of CFS symptoms.43 The safety of low dose glucocorticoids was addressed in a 48 page review article published in last month's ls of Rheumatic Diseases entitled Low-dose glucocorticoid therapy in rheumatoid arthritis- A review on safety: published evidence and prospective trial data. This extensive review assessed

the incidence and severity of adverse effects of long-term low-dose

glucocorticoid therapy in rheumatoid arthritis. This review considered

low dose as any dose below or equivalent to 40 mg hydrocortisone (this

patient received a fraction of this dose 10mg/day). They concluded, "Adverse-effects

of glucocorticoids are abundantly referred to in literature. However,

in the available literature on low-dose glucocorticoid therapy very

little of the commonly held beliefs about their incidence, prevalence

and impact of GC [glucocorticoid] proved to be supported by clear

scientific evidence. Additional data from the randomized controlled

clinical trials reviewed showed that the incidence, severity and impact

of adverse effects of low dose glucocorticoid therapy in rheumatoid

arthritis trials are modest, and often not statistically different to

those of placebo." 10Low dose cortisol has been

shown to improve immunity, as opposed to the well known

immunosuppressive effect of pharmacological doses of glucocorticoids, 23,30,45,46 and has been shown to improve recovery from chronic infections such as EBV.47,22,29In

summary, it is becoming clear that the majority of patients with CFS

and FM suffer from clinically significant adrenocortical dysfunction

and that physiologic replacement of cortisol is an appropriate

intervention in these patients. Cortisol doses of 15-20 mg/day have

been shown to be safe, with little associated risk including adrenal

suppression, and have the potential for significant clinical benefit.

The current evidence supports the use of physiologic doses of cortisol

in the treatment of CFS and FM, and a therapeutic trial of cortisol

should be considered in these patients, especially those with basal

cortisol levels less than 12 ug/dl.Fibromyalgia and Fatigue Centers, Inc16415 Road, Suite 600, TX 75001Phone: 972-788-4001Fax: 972-788-4002Email: info@...References1.

Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP, et

al. Evidence For Impaired Activation of the

Hypothalamic-Pituitary-Adrenal Axis in Patients With Chronic Fatigue

Syndrome. J Clin Endocrinol Metab 1991;73:1224-1234.2. Torpy DJ

et al. Responses of the sympathetic nervous system and the

hypothalamic-pituitary-adrenal axis to interleukin-6 in fibromyalgia.

Arthritis and Rheumatism. 2000; 43: 872-880.3. Calis M, Gokce C.

Investigation of the hypothalamo-pituitary-adreanl axis (HPA) by 1ug

ACTH test and metyrapone test in patients with primary fibromyalgia

syndrome. J Endocrinol Invest 2004 27:42-464. Kirnap M, Colak

REser C, Ozsoy OTutus A, Kelestimur F. A comparison between low-dose (1

microg), standard-dose (250 microg) ACTH stimulation tests and insulin

tolerance test in the evaluation of hypothalamo-pituitary-adrenal axis

in primary fibromyalgia syndrome. Clin Endocrinol (Oxf). 2001

Oct;55(4):455-95. Griep EN, Boersma JW, de Kloet ER. Altered

Reactivity of the Hypothalamic-Pituitary-Adrenal Axis in the Primary

Fibromyalgia Syndrome. J Rheumatol 1993;20:469-746. Jens Gaab,

PhD, Dominik Hüster, MSc, Renate Peisen, MSc, Veronika Engert, BSc,

Vera Sheitz, BSc, Tanja Schad, BSc, H. Schürmeyer, PhD, MD and

Ulrike Ehlert, PhD. Hypothalamic-Pituitary-Adrenal Axis Reactivity in

Chronic Fatigue Syndrome and Shealth Under Psychological,

Physiological, and Pharmacological Stimulation. Psychosomatic Medicine

64:951-962 (2002)7. Cleare AJ, Blair D, Chambers S, Wessely S,

Urinary Free Cortisol in Chronic Fatigue Syndrome Am J Psychiatry

158:641-643, April 20018. Cleare A et al.

Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue

Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy. The

Journal of Clinical Endocrinology & Metabolism 2001.

86(8):3545–3554.9. Cleare AJ et al. Low-dose hydrocortisone in

chronic fatigue syndrome: a randomized crossover trial. Lancet 1999 Feb

6;353(9151):45510. Gaab J, Huster D, Peisen R, Engert V, Schad

T, Schurmeyer TH, Ehlert U. Low-dose dexamethasone suppression test in

chronic fatigue syndrome and health. Psychosom Med. 2002

Mar-Apr;64(2):311-8 11. Altemus M, Dale JK, Michelson D,

Demitrack MA, Gold PW, Straus SE. Abnormalities in response to

vasopressin infusion in chronic fatigue syndrome.

Psychoneuroendocrinology 2001 Feb 1;26(2):175-188 12. LV,

Svec F, Dinan T. A preliminary study of dehydroepiandrosterone response

to low-dose ACTH in chronic fatigue syndrome and in healthy subjects.

Psychiatry Res 2000 Dec 4;97(1):21-2813. LV, Teh J, Reznek

R, A, Sohaib A, Dinan TG. Small adrenal glands in chronic

fatigue syndrome: a preliminary computer tomography study.

Psychoneuroendocrinology 1999 Oct;24(7):759-68 14. Heim C,

Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the

pathophysiology of stress-related bodily disorders.

Psychoneuroendocrinology. 2000 Jan;25(1) 15. LV, Medbak

S, Dinan TG. Desmopressin augments pituitary-adrenal responsivity to

corticotropin-releasing hormone in subjects with chronic fatigue

syndrome and in healthy volunteers. Biol Psychiatry 1999 Jun

1;45(11):1447-5416. De Becker P, De Meirleir K, Joos E, Campine

I, Van Steenberge E, Smitz J, Velkeniers B Dehydroepiandrosterone

(DHEA) response to i.v. ACTH in patients with chronic fatigue syndrome.

Horm Metab Res 1999 Jan;31(1):18-2117. Z Crofford L. The

hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic

fatigue syndrome. J Rheumatol 1998;57 Suppl 2:67-71 18.

Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y,

Kitani T. Dehydroepiandrosterone sulfate deficiency in chronic fatigue

syndrome. Int J Mol Med 1998 Jan;1(1):143-619. LV, Medbak

S, Dinan TG The low dose ACTH test in chronic fatigue syndrome and in

health. Clin Endocrinol (Oxf) 1998 Jun;48(6):733-720. LV,

Medbak S, Dinan TG. Blunted adrenocorticotropin and cortisol responses

to corticotropin-releasing hormone stimulation in chronic fatigue

syndrome. Acta Psychiatr Scand 1998 Jun;97(6):450-45721.

Strickland P, s R, Wearden A, Deakin B A comparison of salivary

cortisol in chronic fatigue syndrome, community depression and healthy

controls. J Affect Disord 1998 Jan;47(1-3):191-194 22. Bender CE. The value of corticosteroids in the treatment of infectious mononucleosis. JAMA 199;529, 196723.

Jefferies W. Mild adrenocortical deficiency, chronic allergies,

autoimmune disorders and the chronic fatigue syndrome: a continuation

of the cortisone story, Med Hypotheses, 1994, Issue: 3, Volume: 42,

Page: 183-9, ISSN: 0306-9877 24. Cleare AJ; Bearn J; Allain T;

McGregor A; Wessely S; Murray RM; O'Keane V. Contrasting neuroendocrine

responses in depression and chronic fatigue syndrome, J Affect Disord,

1995 Aug 18, Issue: 4 Volume: 34 Page: 283-9 25. Moutschen M;

Triffaux JM; Demonty J; Legros JJ; Lefèbvre PJ; . Pathogenic tracks in

fatigue syndromes Acta Clin Belg, 1994, Issue: 6 Volume: 49 Pagination:

274-89 ISSN: 0001-5512 26. Carruthers et al. Myalgic

Encepalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case

Definition, Diagnostic and Treatment Protocols. Journal of Chronic

Fatigue Syndrome.Vol 11(1) 200327. Demitrack MA, Crofford LJ.

Evidence for and pathophysiologic implications of

hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and

chronic fatigue syndrome. Ann N Y Acad Sci 1998 May 1;840:684-69728.

A. McLean,1 A. ,1 E. ,1 Willem J.

Kop,2 H. Groner,1 Kirsten Ambrose,1 K. Lyden,1

H. Gracely,1 J. Crofford,3 E. Geisser,1 Ananda Sen,1

Pinaki Biswas,1 and J. Clauw1. Momentary Relationship Between

Cortisol Secretion and Symptoms in Patients With Fibromyalgia.

Arthritis & Rheumatisim Vol. 52, No. 11, November 2005, pp

3660–3669 29. Manji RJ et al. Depression of cell-mediated immunity durng acute infectious mononucleosis. N Engl J Med 291:1149, 197430. Jefferies W. Cortisol and Immunity. Medical Hypotheses 1991;34:198-20831.

Teitelbaum J, Bird B, Greenfield R, Weiss A, Muenz L, Gould L.

Effective Treatment of Chronic Fatigue Syndrome (CFIDS) &

Fibromyalgia (FMS) - A Randomized, Double-Blind, Placebo-Controlled,

Intent To Treat Study. Journal of Chronic Fatigue Syndrome Volume 8,

Issue 2 – 200132. Takeshita S et al. Intravenous immunoglobulin

preparations promote apoptosis in lipopolysaccharide-stimulated

neutrophils via an oxygen-dependent pathway in vitro. APMIS

2005:113:269-77.33. Wolff FH, Nhuch C, Cadore LP, Glitx CL,

Lhullier F, Furlanetto TW. Low-dose adrenocorticotropin test in

patients with the Acquired Immunodeficiency Syndrome. Braz. J. Infect.

Dis. Apr. 2001, vol.5, no.234. Tordjman K., Jaffe A., Grazas N.

et al. The role of the low dose (1 mg) adrenocorticotropin test in the

evaluation of patients with pituitary diseases. J Clin Endocrinol Metab

1995; 80:1301 5.35. Dickstein G., Schechner C., Nicholson W.E.,

et al. Adrenocorticotropin stimulation test: effects of basal cortisol

level, time of the day, and suggested new sensitive low dose test. J

Clin Endocrinol Metab 1991;72:773-836. Crowley S., Hindmarsh

P.C., Honour J.W., Brook C.G.D. Reproducibility of the cortisol

response to stimulation with a low dose of ACTH (1-24): the effect of

basal cortisol levels and comparison of low dose with high dose

secretory dynamics. J Endocrinol 1993;136:167-7237.

Baraia-Etxaburu Artetxe J., Astigarraga Aguirre B., Elorza Olabegova

R., et al. [Primary adrenal failure and AIDS: report of 11 cases and

review of the literature]. Rev Clin Esp 1998;198:74-9.38.

Zarkovic M., Ciric J., Stojanovic M., et al. Optimizing the diagnostic

criteria for standard (250-mg) and low dose (1-mg) adrenocorticotropin

tests in the assessment of adrenal function. J Clin Endocrinol Metab

1999;84:3170-3. 39. Abdu TA, Elhadd T.A., Neary R., Clayton

R.N. Comparison of the low dose short synacthen test (1 mg), the

conventional dose short synacthen test (250 mg), and the insulin

tolerance test for assessment of the hypothalamo-pituitary-adrenal axis

in patients with pituitary disease. J Clin Endocrinol Metab

1999;84:838-43.40. CH et al. Authors' Response: HPOA

Axis Testing after Pituitary Surgery. Journal of clinical Endocrinology

and Metabolism 2005;90:674441. Riccardo Baschetti, M.D.

Investigations of Hydrocortisone and Fludrocortisone in the Treatment

of Chronic Fatigue Syndrome The Journal of Clinical Endocrinology &

Metabolism Vol. 84, No. 6 2263-226442. Teitelbaum et al. To the

Editor re: McKenzie et al. Low-Dose Hydrocortisone for Chronic Fatigue

Syndrome. 281 No. 20, May 26, JAMA,1999 Vol. 281 No. 20, May 26, 1999.

JAMA May 26, 1999 (281)20:188843. Bou-Holaigah et al. the

relationship between neurally mediated hypotension and the chronic

fatigue syndrome. JAMA 1995;274:961-744. Bashetti R. hydrocortisone and chronic Fatigue Syndrome. Lancet 1999;353:161845.

Grayson J et al. Immunoglobulin production induced in vitro by

glucocorticoid hormones:T-cell dependent stimulation of immunoglobulin

production without B cell proliferation in cultures of human peripheral

blood lympocytes. J clin Invest 68:1539,198146. Jeroen TJ et al.

Altered Glucocorticoid Regulation of the Immune Response in the Chronic

Fatigue Syndrome. ls of the New York Academy of Sciences

917:868-875 (2000)47. Chappel MR. Infectious mononucleosis. Southwest Med 43:253,196248.

Blatman H, Effective Treatment of Fibromyalgia and Mypfacial Pain

Syndrome: A Clinician's Perspective. Journal of the American Academy of

Pain Management. April 2002.