Endocrine
System
Abstract: Chronic fatigue syndrome (CFS) is characterized by severe physical and mental fatigue of central origin. Similar clinical features may occur in disorders of the hypothalamopituitary axis. The aim of the study was to determine whether patients with CFS have abnormalities of the growth hormone/insulinlike growth factor (GH-IGF) axis basally or following hypothalamic stimulation with insulin-induced hypoglycemia. We compared levels of GH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), insulin, and C-peptide in nondepressed CFS patients and normal controls. We found attenuated basal levels of IGF-I (214 ± 17 vs. 263.4 ± 13.4 micrograms/L, p = .036) and IGF-II (420 ± 19.8 vs. 536 ± 24.3 micrograms/L, p = .02) in CFS patients and a reduced GH response to hypoglycemia (peak GH; 41.9 ± 11.5 vs. 106.0 ± 25.6 mU/L, p = .017). Insulin levels were higher (7.6 ± 1.0 vs. 4.3 ± 0.8 mU/L, p = .02) and IGFBP-1 levels were lower (19.7 ± 4.6 vs. 43.2 ± 2.7 mg/L, p = .004) in CFS patients compared with controls. This study provides preliminary data abnormalities of the GH-IGF axis in CFS. It is not apparent whether these changes are components of a primary pathological process or are acquired secondary to behavioral aspects of CFS such as reduced physical activity.
Baschetti R. High androgen levels in chronic fatigue patients [Letter]. Journal of Clinical Endocrinology 1996; 81(7): 2752-3.
Behan PO. Postviral fatigue syndrome [Letter]. British Medical Journal 1992; 304: 1567.
Bennett AL, Chao CC, Hu S, Buchwald D, Fagioli LR, Schur PH, Peterson PK, Komaroff AL. Elevation of bioactive transforming growth factor-beta in serum from patients with chronic fatigue syndrome. Journal of Clinical Immunology 1997; 17(2): 160-66.
Abstract: The level of bioactive transforming growth factor-beta (TGF-beta) was measured in serum from patients with chronic fatigue syndrome (CFS), healthy control subjects, and patients with major depression, systemic lupus erythematosis (SLE), and multiple sclerosis (MS) of both the relapsing/remitting (R/R) and the chronic progressive (CP) types. Patients with CFS had significantly higher levels of bioactive TGF-beta levels compared to the healthy control major depression, SLE, R/R MS, and CP MS groups (P < 0.01). Additionally, no significant differences were found between the healthy control subjects and any of the disease comparison groups. The current finding that TGF-beta is significantly elevated among patients with CFS supports the findings of two previous studies examining smaller numbers of CFS patients. In conclusion, TGF-beta levels were significantly higher in CFS patients compared to patients with various diseases known to be associated with immunologic abnormalities and/or pathologic fatigue. These findings raise interesting questions about the possible role of TGF-beta in the pathogenesis of CFS.
Buchwald D, Umali J, Stene M. Insulin-like growth factor-I (somatomedin C) levels in chronic fatigue syndrome and fibromyalgia. Journal of Rheumatology 1996; 23(4): 739-42.
Abstract: OBJECTIVE. Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are similar conditions characterized by substantial fatigue, diffuse myalgias, sleep disturbances and a variety of other symptoms. Many patients with CFS meet strict criteria for FM. Recently, low insulin-like growth factor-I (IGF-I) levels have been demonstrated in patients with FM, suggesting that disruption of the growth hormone-IGF-I axis might explain the link between the muscle pain and poor sleep. Our goal was to determine whether IGF-I levels are decreased in CFS, and whether such findings are restricted to patients with concurrent FM. METHODS. Radioimmunoassays were used to determine serum concentrations of IGF-I and its binding protein, (IGFBP-3). Subjects were 3 patients seen in a referral clinic for chronic fatigue: 15 patients with CFS, 15 who met criteria for both CFS and FM (CFS-FM), 27 with FM alone; and 15 healthy control (HC) subjects. RESULTS. Patients and control subjects had similar demographic and clinical characteristics. No significant differences were observed among any of the 3 patient groups and control subjects in the mean concentration of either IGF-I or IGFBP-3. Likewise, the proportion of subjects with values above or below the laboratory's reference range did not differ for IGF-I or IGFBP-3. CONCLUSIONS. These findings suggest the disruption of the growth hormone-IGF-I axis previously demonstrated in FM patients is not evident in a referral population of patients with CFS, CFS-FM, or FM.
Cleare AJ, O'Keane V. Endocrine responses to fenfluramine challenge in chronic fatigue syndrome. Canadian Journal of Psychiatry 1996; 41(2) : 129-31.
Curtis D, Bullock T. Postviral fatigue syndrome [Letter]. British Medical Journal 1992; 304: 1566-67.
Dinan TG, Majeed T, Lavelle E, Scott LV, Berti C, Behan P. Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychoneuroendocrinology 1997; 22(4): 261-7.
Abstract: We examined 5HT1a-mediated ACTH release in patients with chronic fatigue syndrome (CFS) using a between-subjects design. Patients attending a specialist outpatient clinic for CFS, who fulfilled CDC criteria, together with age- and sex-matched healthy comparison subjects, were recruited. Subjects had a cannula inserted in a forearm vein at 0830 h and were allowed to relax until 0900 h, when baseline bloods for ACTH and cortisol were drawn. They were then given ipsapirone 20 mg PO and further blood for hormone estimation was taken at +30, +60, +90, +120 and +180 min. Baseline ACTH and cortisol levels did not differ between the two groups. Release of ACTH (but not cortisol) in response to ipsapirone challenge was significantly blunted in patients with CFS. We conclude that serotonergic activation of the hypothalamic-pituitary-adrenal axis is defective in CFS. This defect may be of pathophysiological significance.
Goldberg M, Lichten J. High androgen levels in chronic fatigue patients [Letter]. Journal of Clinical Endocrinology and Metabolism 1995; 80(11): 3390-1.
Grufferman RA, Stone NL, Eby MS, Huang SB, Muldoon SB, Penkower L. Closeness of contacts between people in two clusters of chronic fatigue syndrome: evidence for an infection etiology? [Abstract]. Clinical Infectious Diseases 1994; 18(Supp 1): S54-S55.
Hatcher S. Postviral fatigue syndrome [Letter]. British Medical Journal 1992; 304: 1566.
Jeffries WMcK. Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story. Medical Hypotheses 1994; 42, 3: 183-189.
Abstract: The possibility that patients with disorders that improve with administration of large, pharmacologic dosages of glucocorticoids, such as chronic allergies and autoimmune disorders, might have mild deficiency of cortisol production or utilization has received little attention. Yet evidence that patients with rheumatoid arthritis improved with small, physiologic dosages of cortisol or cortisone acetate was reported over 25 years ago, and that patients with chronic allergic disorders or unexplained chronic fatigue also improved with administration of such small dosages was reported over 15 years ago, suggesting that these disorders might be associated with mild adrenocortical deficiency. The apparent reasons for the failure of these reports to be confirmed or mentioned in medical textbooks and the facts needed to restore perspective are reviewed, and the need for further studies of the possible relationship of a mild deficiency of the production or utilization of cortisol and possibly other normal adrenocortical hormones to the development of these disorders is discussed.
Leese G, Chattington P, Fraser W, Vora J, Edwards R, Williams G. Short-term night-shift working mimics the pituitary-adrenocortical dysfunction in chronic fatigue syndrome. Journal of Clinical Endocrinology and Metabolism 1996; 81(5): 1867-1870.
Abstract: The purpose of this study was to determine whether a short period (5 days) of night-shift work affected the pituitary-adrenal responses to CRH. Ten nurses (8 female and 2 male; age 28.1 ± 1.7 yr: mean ± SEM) working at the Royal Liverpool University Hospital, and who regularly undertook periods of night and day shift work were enrolled. Measurements were made of basal ACTH and cortisol concentrations, and their responses to iv ovine CRH (1 microgram.kg-1). Basal ACTH concentrations were higher during the night shift than during the day shift (12.9 ± 5.1 pmol.L-1 vs. 4.7 ± 1.2 pmol.L-1, P < 0.01) whereas cortisol concentrations were lower (551 ± 48 nmol.L 1 vs. 871 ± 132 nmol.L 1, P < 0.01). After CRH injection, ACTH concentrations remained consistently higher during the night shift, but the integrated increase in ACTH concentration was lower (P < 0.05) than during the day shift. Conversely, the increase in cortisol concentration was greater during the night shift than the day shift (283 ± 53 nmol.L-1 vs. 134 ± 41 nmol.L-1, P < 0.05). We conclude that the pituitary-adrenal responses to CRH are markedly disrupted after only 5 days of nighttime work. These abnormalities mimic those previously observed in patients with chronic fatigue syndrome. Neuroendocrine abnormalities reported to be characteristic of chronic fatigue syndrome may be merely the consequence of disrupted sleep and social routine.
Lieberman J, Bell DS. Serum angiotensin-converting enzyme as a marker for the chronic fatigue-immune dysfunction syndrome: a comparison to serum angiotensin-converting enzyme in sarcoidosis. American Journal of Medicine 1993; 95(4): 407-12.
Abstract: PURPOSE: To study the reliability of a serum angiotensin-converting enzyme (ACE) assay as a marker for the chronic fatigue-immune dysfunction syndrome (CFIDS), and to compare some enzyme characteristics of ACE in CFIDS with that in sarcoidosis. PATIENTS AND METHODS: Forty-nine patients with CFIDS and 56 endemic control subjects from Lyndonville, New York, and Charlotte, North Carolina; plus 23 untreated patients with active sarcoidosis, 24 with sarcoidosis receiving corticosteroid therapy, and 32 patient controls without sarcoidosis from California. Serum ACE levels were determined with a spectrophotometric method. The effect of freezing and thawing and the effect of storage at 4 degrees C were compared between CFIDS and sarcoidosis samples. RESULTS: Serum ACE levels were elevated in 80% of patients with CFIDS and 30% of endemic control subjects as compared with 9.4% of nonendemic California control subjects. The ACE activity in CFIDS differed from that in sarcoidosis because of its lability with storage at 4 degrees C in CFIDS and its partial activation with freezing and thawing. Thus, ACE activity was elevated in the majority of CFIDS patients either upon initial assay or upon a subsequent assay after refreezing. ACE activity was elevated in 87% of patients with active sarcoidosis and was not affected by storage or freezing and thawing. CONCLUSIONS: Serum ACE elevations may be a useful marker for CFIDS, especially if a method can be developed to distinguish ACE in CFIDS from that in sarcoidosis. The sensitivity for CFIDS was 80%, with 68% specificity in an endemic area. The increased prevalence of serum ACE elevations in endemic controls as compared with nonendemic controls suggests that an ACE increase may be an early manifestation of CFIDS and supports the concept that CFIDS is a definite disease state.
Majeed T, Dinan TG, Behan PO. Baclofen-induced growth hormone release: does the GABA play any role in the pathophysiology of chronic fatigue syndrome? Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 119-120.
Abstract: OBJECTIVES. Recent evidence has suggested the involvement of the GABAergic system in depression. In the present study the sensitivity of GABA-B receptors was assessed via the growth hormone response to baclofen to find out the role, if any, of GABAergic mechanisms in the pathophysiology of CFS. METHODS. Twelve healthy controls (mean age 35 years) and 12 patients (mean age 39 years) who met CDC criteria for CFS were recruited in this study. All gave their informed consent to participate in the study. The experiment was performed in the morning after an overnight fast. Serial blood samples were taken for growth hormone estimation at 0, +30, +60, +120, and +180 min after the administration of baclofen (20 mg orally). Change in growth hormone (DGH) was measured by subtracting the baseline GH level from the peak value after baclofen administration. RESULTS. The overall GH levels rose after baclofen administration. The response was not different significantly in patients with chronic fatigue syndrome (mean DGH = 12.6 Mu/l) from controls (mean DGH = 10.8 Mu/l), P=0.580. CONCLUSION. No difference was found between healthy subjects and CFS patients with regard to the GH response to acute administration of baclofen suggesting GABAergic mechanisms are not involved in the pathophysiology of CFS.
Majeed T, Dinan TG, Thakore J, Gray C, Behan PO. Defective dexamethasone induced growth hormone release in chronic fatigue syndrome: evidence for glucocorticoid receptor resistance and lack of plasticity? Journal of Irish Colleges of Physicians and Surgeons 1995; 24, 1: 20-24.
Pizzigallo E, Barberio A, Racciatti D, De Remigis PL, Sensi S. Circadian variations of prolactin (PRL), thyrotropic hormone (TSH), adrenocorticortropic hormone (ACTH) and cortisol (CS) in the chronic fatigue syndrome (CFS). Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 120-121.
Abstract: OBJECTIVE. The clinical features of CFS patients include signes of hypothalamic dysfunction, such as body temperature dysregulation, hypersensitivity to cold, appetite variation, fluid retention, irregular menstruation, hot flashes, excessive sweating and sleep distrubances. The hypothalamus controls some rhythmic functions, particularly hormones. In the CFS some describe a dysfunction of hypothalamo-pituitary-adrenal axia. We therefore elevated the PRL, TSH, ACTH and CS variations during the 24 hours to verify possible alterations of circadian rhythm in CFS patients, or at least in a subgroup of them, as a further indication of hypothalamic dysfunction. METHODS. We examined 13 patients (9 F and 4 M, mean age: 34.8 and 35.7 respectively), enrolled in CFS study on the basis of CDC criteria (1988-1994). The illness followed an acute viral infection in 3 of them (35%) (flu-like syndrome I one patient, mononucleosis syndrome in another, and acute respiratory infection in the third). All the examined patients complained of neurophyschical disturbances. For each patient, hospitalization was necessary in order to collect 6 different blood samples every four hours during a twenty-four hour period. We detected PRL, CS and TSH by fluorometric enzyme immunoassay (Baxter Diagnostic Inc.) and ACTH by immunoradiometric assay (Henning Berlin GMBH). RESULTS. The table shows our results for each hormone during the 24 hours. Cortisol showed a peak in the morning (h 08) and a minimum serum concentration in the evening (h 20/24), which agrees with ACTH rhythm behavior. Prolactin showed a peak in the evening (h 20/24), which agrees with the influence of REM sleep periods on prolactin secretion. Finally, TSH presented circadian fluctuations with a peak in the first evening period. Thus, the behavior of the circadian hormonal variations observed in the CFS patients in our Center is comparable with that of healthy subjects. CONCLUSION. Although many have reported alterations of HPA axis in CFS patients due to a central (hypothalamic) origin with CRH deficiency, our results did not reveal alterations in the CS, ACTH, TSH and PRL circadian rhythms. Indeed the present study suggests a persistence of hypothalamic control on hormonal rhythmic functions in CFS patients. Nevertheless, these findings cannot allow us to deny the possible involvement of the hypothalamus in CFS pathogenesis, since a selective dysfunction of this gland can be reflected in changes of specific activities usually controlled by the hypothalamus.
Richardson J. Disturbance of hypothalamic function and evidence for persistent enteroviral infection in patients with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 1995; 1(2): 59-66.
Abstract: It has been suggested that one of the major effects of persistent virus infections in the production of disorders such as the chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is on the hypothalamus (1). Buspirone, which is one of the anxiolytic drugs of the azapyrone group, causes a release of prolactin by stimulation of serotonin 5-hydroxytryptamine (5-HT) receptors. The buspirone-prolactin response was studied in a subgroup of patients with CFS/ME and evidence of persistent enteroviral infection, as shown by the repeated detection of the group-specific protein of enteroviruses, VP1, in the blood. Family controls who were asymptomatic were studied at the same time. In addition to the response to buspirone, diurnal variations in cortisol and prolactin levels were studied. It was found that the patients with CFS/ME had much greater rises in prolactin levels one hour after buspirone compared to controls. Cortisol levels were elevated in the patients, but the rise was not significantly different between the two groups. There was a significant association between the pattern of sleep disturbance, which we speak of as the OWL syndrome, and the ratio of pre- and post-buspirone prolactin levels. This study shows that there is a hypothalamic disturbance in the patients who also had evidence of enteroviral infection as part of the disorder of CFS/ME. It represents a quantifiable biochemical alteration to be found in this group of patients.
Sharpe M, Clements A, Hawton K, Young AH, Sargent P, Cowen PJ. Increased prolactin response to buspirone in chronic fatigue syndrome. Journal of Affective Disorders 1996; 41: 71-76.
Abstract: We studied the endocrine and subjective responses that followed acute administration of the 5-HT1A receptor agonist buspirone (0.5 mg/kg orally) in 11 male patients with chronic fatigue syndrome (CFS) and a group of matched healthy controls. Patients with CFS had significantly higher plasma prolactin concentrations and experienced more nausea in response to buspirone than did controls. However, the growth hormone response to buspirone did not distinguish CFS patients from controls. Our data question whether the enhancement of buspirone-induced prolactin release in CFS is a consequence of increased sensitivity of post-synaptic 5-HT1A receptors. It is possible that the increased prolactin response to buspirone in CFS could reflect changes in dopamine function.
Williams G, Pirmohamed J, Minors D, Waterhouse J, Buchan I, Arendt J, Edwards RHT. Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndorme. Clinical Physiology 1996; 16(4): 327-337.
Abstract: Many patients with chronic fatigue syndrome (CFS) display features of hypothalamic dysfunction. We have investigated aspects of circadian rhythmicity, an important hypothalamic function, in 20 CFS patients and in 17 age- and sex-matched healthy control subjects. There were no differences between the two groups in the amplitude, mesor (mean value) or timing of the peak (acrophase) of the circardian rhythm of core temperature, or in the timing of the onset of melatonin secretion. However, the CFS patients showed no significant correlation between the timing of the temperature acrophase and the melatonin onset (P <0.5), whereas the normal significant correlation was observed in the controls (P < 0.05). Dissociation of circadian rhythms could be due to the sleep deprivation and social disruption, and/or the reduction in physical activity which typically accompany CFS. By analogy with jet-lag and shift-working, circadian dysrhythmia could be an important factor in initiating and perpetuating the cardinal symptoms of CFS, notably tiredness, impaired concentration and intellectual impairment.
Yamaguti K, Kuratsune H, Machi T, Kodate S, Kinani T. Abnormality of adrenal function in the patients with CFS: the decline of 17-ketosteroid sulfate (17KS-S). Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 124-125.
Abstract: The etiology of CFS has not yet been clarified although many investigators have made efforts to resolve this problem using a number of approaches. In 1991, Demitrack et al. Reported that patients with CFS might have impaired activation of the hypothalamic-pituitary-adrenal axis. It is also well known that during psychological stress serum cortisol concentration and urinary 17-hydroxycoritco-steroid (17-OHCS) excretion increase, while urinary 17-ketosteroid sulfate (17-KS-S) excretion decreases. To investigate the endocrine relationship between psychological and physical stress and CFS, we compared the values of urinary 17-OHCS (mg/g creatinine) and 17-KS-S (mg/gcreatinine) excretion in 49 patients with CFS (26 ± 3.6 years old) and in 35 normal age-matched controls (27 ± 3.9 years old) while they were sleeping at night. We found that the level of 17-KS-S was significantly lower in CFS patients than in normal controls. (1.54 ± 1.04 in CFS vs 3.01 ± 1.04 in control, p<0.001), while the level of 17-OHCS was about the same as the controls (4.31 ± 1.26 in CFS vs 4.22 ± 0.77 in controls). To clarify the abnormality of 17-KS-S in the patients with CFS, we measured the serum level of ACTH, cortisol, 17-OH pregnenolone, dehydroepiandrosterone (DHEA), DHEA-sulphate (DHEA-S) and androstenedione after overnight fasting in 14 patients. The level of ACTH, cortisol, 17-OH pregnenolone and androstenedione in most patients with CFS was within the range of mean ± 2SD of normal controls, while the level of DHEA decreased in some patients and the level of DHEA-S decreased in most patients with CFS. These results suggest that the decline of urinary 17-KS-S excretion while sleeping at night in the patients with CFS was mainly due to the decline of serum DHEA-S. These abnormalities found in CFS are quite different from those found in patients with mental and physical diseases reported previously.