Category: Endocrine System

Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion

Abstract:

OBJECTIVE: Previous studies have suggested that chronic fatigue syndrome (CFS) is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS.

DESIGN: (i) A comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo-controlled crossover study of the effects of hydrocortisone on leptin levels in CFS.

PATIENTS: Thirty-two medication free patients with CFS but not comorbid depression or anxiety. Thirty-two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls.

MEASUREMENTS: We measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo-controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo.

RESULTS: At baseline, there was no significant difference in plasma leptin between patients [mean 13.8, median 7.4, interquartile range (IQR) 18.0 ng/ml] and controls (mean 10.2, median 5.5, IQR 11.3 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment-responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone-induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS.

CONCLUSIONS: We conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.

 

Source: Cleare AJ, O’Keane V, Miell J. Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion. Clin Endocrinol (Oxf). 2001 Jul;55(1):113-9. http://www.ncbi.nlm.nih.gov/pubmed/11453960

 

Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors

Abstract:

BACKGROUND: In this study we tested the hypothesis that the increased sensitivity to glucocorticoids in chronic fatigue syndrome (CFS)-patients can be attributed to an altered functioning of their glucocorticoid receptors (GR).

METHODS: For this purpose, affinity and distribution of the GR were studied in purified, peripheral blood mononuclear cells (PBMC) of 10 CFS patients and 14 controls along with the responsiveness of these cells to glucocorticoids in vitro.

RESULTS: Affinity (Kd) and number of GR was not different in PBMC of CFS patients when compared with the controls (Kd, 12.9 +/- 8.9 nmol vs 18.8 +/- 16.2 nmol and GR number, 4,839 +/- 2,824/ cell vs 4,906 +/- 1,646/cell). Moreover, RT-PCR revealed no differences in GR messenger RNA expression. Nevertheless, PBMC from CFS patients showed an increased sensitivity to glucocorticoids in vitro. In CFS patients 0.01 micromol dexamethasone suppressed PBMC proliferation by 37%, whereas the controls were only suppressed by 17% (P < 0.01). Addition of phorbol 12-myristate 13-acetate to the cultures rendered the cells resistant to dexamethasone with regard to proliferation and IL-10 and IFN-gamma production, but not to IL-2 and TNF-alpha production in both patients and controls. No difference between patients and controls was observed in this respect

CONCLUSIONS: In conclusion, PBMC of CFS patients display an increased sensitivity to glucocorticoids, which cannot be explained by number or affinity of the GR but should rather be attributed to molecular processes beyond the actual binding of the ligand to the GR.

 

Source: Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L. Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors. J Investig Med. 2001 Mar;49(2):195-204. http://www.ncbi.nlm.nih.gov/pubmed/11288761

 

Urinary free cortisol in chronic fatigue syndrome

Abstract:

OBJECTIVE: The authors measured 24-hour urinary free cortisol in a group of well-characterized patients with chronic fatigue syndrome.

METHOD: They obtained 24-hour urine collections from 121 consecutive clinic patients with chronic fatigue syndrome and 64 comparison subjects without the syndrome.

RESULTS: 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. Lower levels of urinary free cortisol were not related to medication use, sleep disturbance, or disability levels.

CONCLUSIONS: There is mild hypocortisolism in chronic fatigue syndrome. Whether a primary feature or secondary to other factors, hypocortisolism may be one factor contributing to the symptoms of chronic fatigue syndrome.

 

Source: Cleare AJ, Blair D, Chambers S, Wessely S. Urinary free cortisol in chronic fatigue syndrome. Am J Psychiatry. 2001 Apr;158(4):641-3. http://www.ncbi.nlm.nih.gov/pubmed/11282703

 

Secretion of growth hormone in patients with chronic fatigue syndrome

Abstract:

Decreased serum levels of insulin-like growth factor I (IGF-I) are common in patients with fibromyalgia, which is frequently associated withchronic fatigue syndrome (CFS). Twenty patients with CFS (7 men, 13 women; age range, 30-60 years) and age- and sex-matched controls were tested for peak GH responses to insulin-induced hypoglycaemia and arginine administration. Nocturnal secretion of GH and serum levels of IGF-I were also measured. Serum IGF-I SDS (+/- SD) was significantly lower in patients with CFS than in controls (SDS, -0.39 +/- 1.07 vs 0.33 +/- 0.84; P = 0.02). Patients with CFS also tended to have reduced nocturnal secretion of GH (area under the curve, 32.4 +/- 18.3 vs 62.7 +/- 43.7 microg/l/15 minutes; P= 0.06), but peak GH responses to insulin-induced hypoglycaemia and arginine administration did not differ significantly between the two groups. It is not clear whether the tendency for impaired spontaneous nocturnal GH secretion in patients with CFS is a cause or an effect of the condition.

 

Source: Berwaerts J, Moorkens G, Abs R. Secretion of growth hormone in patients with chronic fatigue syndrome. Growth Horm IGF Res. 1998 Apr;8 Suppl B:127-9. http://www.ncbi.nlm.nih.gov/pubmed/10990147

 

Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome

Abstract:

OBJECTIVE: Previous studies have revealed that hormonal disturbances may accompany the chronic fatigue syndrome (CFS). Changes in the secretion of the pituitary-adrenal axis have been demonstrated, as well as abnormalities in the GH-IGF-I axis. However, data have not always been well characterized and were sometimes conflicting. The small number of CFS patients investigated in earlier studies may have played a role in the interpretation of the results.

SUBJECTS AND DESIGN: Hormonal testing was performed in 73 nonobese CFS patients and nonobese 21 age-and gender-matched healthy controls. We investigated GH, ACTH and cortisol responses to insulin-induced hypoglycaemia. In a subgroup of patients arginine and clonidine stimulation for GH was also performed. Nocturnal secretion of GH, ACTH and cortisol were determined. Serum levels of IGF-I, prolactin, TSH, and free thyroxine were also measured. Visceral fat mass was assessed by CT scanning.

RESULTS: GH response to insulin induced hypoglycaemia assessed by peak value (17.0 +/- 13.1 microg/l vs. 22. 1 +/- 9.8 microg/l; P = 0.01) and by AUC (450.0 +/- 361.3 microg/l vs. 672.3 +/- 393.0 microg/l; P = 0.002) was significantly decreased in CFS patients vs. controls. Nocturnal GH secretion assessed by GH peak value (5.4 +/- 3.7 vs. 9.0 +/- 5.1 microg/l; P = 0.44) and by AUC (34.4 +/- 20.2 vs. 67.4 +/- 43.1; P = 0.045) was also significantly impaired in CFS patients. Arginine and clonidine administration showed no differences in GH secretion between CFS patients and controls. In the CFS group, GH peak values were significantly higher after ITT than after arginine (P = 0.017) or clonidine (P = 0.001). No differences in serum IGF-I levels were found between CFS patients and controls. Except for a significantly lower nocturnal cortisol peak value, no differences were found in ACTH and cortisol secretion between CFS patients and controls. Significantly higher serum prolactin levels (7.4 +/- 4.7 microg/l vs. 4.4 +/- 1.3 microg/l; P = 0.004) and significantly higher serum TSH levels (1.6 +/- 1.0 mU/l vs. 1.0 +/- 0.4 mU/l; P = 0.011) were found in CFS patients. Serum free thyroxine was comparable in both groups. Visceral fat mass was significantly higher in CFS patients (86.6 +/- 34.9 cm2 vs. 51.5 +/- 15.7 cm2; P < 0.001).

CONCLUSIONS: We observed a significant impairment of GH response during insulin-induced hypoglycaemia and a low nocturnal GH secretion in CFS patients. These changes did, however, not lead to different concentrations in serum IGF-I. The clinical expression of this inadequate GH secretion can thus be questioned, although the alteration in body composition may be related to this relative GH deficiency. Significantly increased prolactin and TSH levels were found when compared to controls. These findings give support to the hypothesis of a decreased dopaminergic tone in CFS. Further investigations are required in order to identify specific adaptations within the neurotransmitter system in CFS and to determine the clinical importance of the impaired GH homeostasis.

 

Source: Moorkens G, Berwaerts J, Wynants H, Abs R. Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome. Clin Endocrinol (Oxf). 2000 Jul;53(1):99-106.http://www.ncbi.nlm.nih.gov/pubmed/10931086

 

Chronic fatigue syndrome: a form of Addison’s disease

Dear Sir, Evengård et al.’s article [1] on chronic fatigue syndrome (CFS) is disappointing, because in their review, despite its 15 pages and 165 references, there is not a single word about the staggering similarity between CFS and Addison’s disease. As someone whose CFS symptoms resolved dramatically with an old remedy for Addison’s disease [2], I understandably found that review even more disappointing.

To compensate for Evengård et al.’s failure to mention both the impressive overlap of CFS with Addison’s disease and its clinical implications, I summarize here these issues.

CFS and Addison’s disease share 36 features [3–6]. Three others, however, are to be added. In fact, reduction in adrenal gland size [7], antibodies against the adrenal gland [8] and respiratory muscle dysfunction [9], besides being present in CFS [7–9], have also been found in Addison’s disease [10–12]. In view of the 39 features that CFS shares with Addison’s disease [3–12] (see Table 1), which constitute a similarity between two distinctly named diseases that is probably unequalled in the medical literature, it seems arguable that CFS should practically be viewed as a form of Addison’s disease [13]. One could object that CFS patients, unlike Addisonian subjects, do not display hyperpigmentation or basal hypocortisolaemia. Neither abnormality, however, is a constant presenting feature of Addison’s disease [14].

You can read the rest of this comment here: http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2000.00695.x/full

 

Source: Baschetti R. Chronic fatigue syndrome: a form of Addison’s disease. J Intern Med. 2000 Jun;247(6):737-9. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2000.00695.x/full (Full article)

 

Follicular phase hypothalamic-pituitary-gonadal axis function in women with fibromyalgia and chronic fatigue syndrome

Abstract:

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are clinically overlapping stress associated disorders. Neuroendocrine perturbations have been noted in both syndromes, and they are more common in women, suggesting abnormalities of gonadal steroid hormones. We tested the hypothesis that women with FM and CFS manifest abnormalities of the hypothalamic-pituitary-gonadal (HPG) hormonal axis.

METHODS: We examined the secretory characteristics of estradiol, progesterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH), including a detailed analysis of LH in premenopausal women with FM (n = 9) or CFS (n = 8) during the follicular phase of the menstrual cycle compared to matched healthy controls. Blood was collected from an indwelling intravenous catheter every 10 min. over a 12 h period. LH was assayed from every sample; pulses of LH were identified by a pulse-detection program. FSH and progesterone were assayed from a pool of hourly samples for the 12 h period and estradiol from samples pooled over four 3 h time periods.

RESULTS: There were no significant differences in FSH, progesterone, or estradiol levels in patients versus controls. There were no significant differences in pulsatile secretion of LH.

CONCLUSION: There is no indication of abnormal gonadotropin secretion or gonadal steroid levels in this small, but systematic, study of HPG axis function in patients with FM and CFS.

 

Source: Korszun A, Young EA, Engleberg NC, Masterson L, Dawson EC, Spindler K, McClure LA, Brown MB, Crofford LJ. Follicular phase hypothalamic-pituitary-gonadal axis function in women with fibromyalgia and chronic fatigue syndrome. J Rheumatol. 2000 Jun;27(6):1526-30. http://www.ncbi.nlm.nih.gov/pubmed/10852283

 

Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome

Abstract:

GH deficiency states and chronic fatigue syndrome (CFS) share several characteristics, and preliminary studies have revealed aspects of GH dysfunction in CFS.

This study assessed indexes of GH function in 37 medication-free CFS patients without comorbid psychiatric illness and 37 matched healthy controls. We also assessed GH function before and after treatment with low dose hydrocortisone, which has been shown recently to reduce fatigue in CFS. We measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH excretion. We also performed 2 dynamic tests of GH function: a 100-microg GHRH test and an insulin stress test using 0.15 U/kg BW insulin.

There were no differences between patients and controls in basal levels of IGF/IGFBP or in urinary GH excretion. GH responses to both the GHRH test and the insulin stress test were no different in patients and controls.

CFS patients did have a marginally reduced suppression of IGFBP-1 during the insulin stress test. Hydrocortisone treatment had no significant effect on any of these parameters. There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone treatment appears to have little impact on GH function.

 

Source: Cleare AJ, Sookdeo SS, Jones J, O’Keane V, Miell JP. Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 2000 Apr;85(4):1433-9. http://www.ncbi.nlm.nih.gov/pubmed/10770178

 

Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome

Abstract:

The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls.

Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients.

We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.

 

Source: Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ. Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. J Clin Endocrinol Metab. 2000 Feb;85(2):692-6. http://www.ncbi.nlm.nih.gov/pubmed/10690878

 

The 1microg short Synacthen test in chronic fatigue syndrome

Abstract:

OBJECTIVE: Many studies suggest mild hypocortisolism in chronic fatigue syndrome (CFS), usually assumed to be due to reduced suprahypothalamic drive to the hypothalamo-pituitary-adrenal (HPA) axis. We wished to explore further the state of the HPA axis in CFS using the 1 microg low dose short Synacthen test.

DESIGN: Subjects received an intravenous bolus of 1 microg Synacthen; samples for cortisol estimation were taken at baseline and 2, 10, 20, 30, 40 and 60 minutes after injection.

PATIENTS: We tested 20 subjects suffering from CFS according to the criteria of the Center for Diseases Control without psychiatric comorbidity and 20 matched healthy controls. All subjects were drug free for at least 1 month.

MEASUREMENTS: We calculated the cortisol responses to the test as the maximum cortisol attained, the incremental rise in cortisol over baseline (Deltavalue) and as the integrated area under the curve.

RESULTS: There were no significant differences in baseline cortisol or cortisol responses between patients and controls. However, responses generally were low, and many subjects’ peak responses were prior to the standard 30 minute sampling time.

CONCLUSIONS: These results do not lend support to the theory that patients with chronic fatigue syndrome have a low adrenal reserve. However, results from studies assessing the HPA axis are proving to be inconsistent. We suggest that many other factors may be contributing to HPA axis alterations in chronic fatigue syndrome, including sleep disturbance, inactivity, altered circadian rhythmicity, illness chronicity, concomitant medication and comorbid psychiatric disturbance. These sources of heterogeneity need to be considered in future studies, and may explain the inconsistent findings to date.

Comment in: The 1microg Synacthen test in chronic fatigue syndrome. [Clin Endocrinol (Oxf). 2000]

 

Source: Hudson M, Cleare AJ. The 1microg short Synacthen test in chronic fatigue syndrome. Clin Endocrinol (Oxf). 1999 Nov;51(5):625-30. http://www.ncbi.nlm.nih.gov/pubmed/10594524