Joan Butler

NEUROENDOCRINE RESPONSES TO D-FENFLURAMINE AND INSULIN-INDUCED HYPOGLYCEMIA IN CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome (CFS) is a disorder characterized by severe physical and mental fatigue and fatiguability of central rather than peripheral origin. We hypothesized that CFS is mediated by changes in hypothalamopituitary function and so measured the adrenocorticotrophic hormone (ACTH), cortisol, growth hormone, and prolactin responses to insulin-induced hypoglycemia, and the ACTH, cortisol, and prolactin responses to serotoninergic stimulation with dexfenfluramine in nondepressed CFS patients and normal controls. We have shown attenuated prolactin responses to hypoglycemia in CFS. There was also a greater ACTH response and higher peak ACTH concentrations (36.44 +/- 4.45 versus 25.60 +/- 2.78 pg ml), whereas cortisol responses did not differ, findings that are compatible with impaired adrenal cortical function. This study provided evidence for both pituitary and adrenal cortical impairment in CFS and further studies are merited to both confirm and determine more precisely their neurobiological basis so that rational treatments can be evolved.

Changes in growth hormone, insulin, insulinlike growth factors (IGFs), and IGF-binding protein-1 in chronic fatigue syndrome

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.

Biochemical tests of growth hormone status in short children.

There are several thousand published papers on biochemical testing of growth hormone status in children, an indication of the confused and inconclusive state of the subject. The size of the literature forced the restriction of the author’s intended systematic review to English-language papers published since 1974 (or later, for some parts of the review). Retrieval of papers via the British Medical Association library was limited by the considerable number of journal issues missing and by the copyright laws. In all, about 600 papers were acquired, including some from the King’s College School of Medicine library and the interlibrary loan system. The review is therefore far from complete. The evaluation of growth hormone (GH) status is complicated by many factors. Firstly, the secretion of GH is controlled by many general variables such as food intake, exercise, sleep and stress, and by factors such as age, body mass index, gender and pubertal stage. Secondly, the neuroendocrine control mechanisms are not yet fully elucidated. GH concentrations in blood are characterized by large pulses succeeded by very low levels, the largest pulses being seen during sleep. Thirdly, GH is not a single substance, there being the major 22 kDa species and a 20 kDa splice variant, and the extracellular domain of the tissue receptor appears in blood as a GH binding protein. The consensus of GH assays was and still is poor, and the effect of the GH binding protein on GH assays is poorly characterized. The de®nition of a short child is not simple. Although compiled from data on thousands of children, charts of height and height velocity versus age for normal children are least accurate at the extremes, where the numbers of subjects are low and the curve ®t poor. There is a need for regular reassessment to allow for secular trends, which at present would re ect greater adult height and earlier puberty. Prediction of adult height from mid-parental height is unreliable. Calculation of height velocity is inaccurate over periods of less than 6 months, as height velocity is not constant and errors of height measurement will contribute disproportionately. The third centile for height has commonly been used as the cut-off for short stature. A height velocity around the 25th centile is needed to maintain a position on the height centile chart. One of the major problems is that there is no `gold standard’ biochemical de®nition of growth hormone de®ciency (GHD) and only severe cases are recognizable clinically. Estimations of the 24-h or 12-h secretion rate from the area under the curve of plasma GH versus time have been largely invalidated by the insensitive immunoassays used. Continuous or intermittent sampling techniques are cumbersome and invasive procedures involving hospital admission, and the sampling frequency may introduce large errors. The same dif®culties have impeded the use of the plasma GH response to exercise or pulse amplitudeduring sleep. Estimation of 24-h, or more commonly overnight, urinary GH excretion requires very sensitive (immunometric) GH assays, which have been developed only recently.Moreover, urinary GH shows very high day-to-day variation. Provocation tests offered shorter and more controllable testing regimes, but until very recently data on normal children were lacking, for obvious ethical reasons. Various arbitrary cut-offs have been used, with little regard for the nature of the stimulant. These cut-offs were originally established to ration the meagre supplies of pituitary-derived GH for treatment and have changed with increasing availability of recombinant GH. Variable responses are found in all groups of subjects, and normal children Evidence-based Review Ann Clin Biochem 2001; 38: 1±2

Serum Prolactin Bioactivity and Immunoactivity in Hyperprolactinaemic States

Serum prolactin concentrations were measured using a sensitive bioassay (Nb2 assay) and by radioimmunoassay in 11 patients with prolactin-secreting pituitary tumours (median serum immunoactive prolactin 5150 mU/L), and in 58 normal control subjects (median prolactin 190 mU/L). The mean ratio of serum prolactin bioactivity to immunoactivity was significantly lower in patients with prolactinomas than in normoprolactinaemic controls. Ten lactating women in the early post-partum period (median prolactin 3800 mU/L), studied as a model of physiological hyperprolactinaemia, also had reduced bioactivity to immunoactivity ratios. Overall, there was a significant negative correlation between bioactivity : immunoactivity ratio and serum immunoactive prolactin. The change in relative bioactivity of prolactin in serum samples from patients with prolactinomas and in women with physiological hyperprolactinaemia may reflect changes in the molecular heterogeneity of the hormone. Such changes may affect activity in both bioassays and radioimmunoassays.

Biological Activity of Serum Prolactin in Patients with Primary Hypothyroidism

Prolactin bioactivity was measured in sera from 22 patients with primary hypothyroidism and 13 euthyroid control subjects and compared with estimates of immunoactivity given by radioimmunoassay. The Nb2 rat lymphoma cell assay was modified to improve specificity for prolactin and used to measure bioactivity. Results of serum prolactin levels obtained using the bioassay were closely correlated with radioimmunoassay results in both hypothyroid patients and control subjects. Mean bioactivity/immunoactivity ratios in patients were not significantly different from those in control subjects. Mean prolactin concentration measured by both assays was significantly higher in patients than control subjects. Serum prolactin in patients with primary hypothyroidism appears to have essentially normal bioactivity as measured in the Nb2 assay, in contrast with a report of major differences between activity in radioreceptor assay and RIA in hypothyroid patients.

Serum Thyrotrophin in Patients with Destructive Pituitary Lesions Assessed by a Sensitive Immunoradiometric Assay

Using a sensitive immunoradiometric assay, serum concentrations of thyrotrophin (TSH) were measured both basally and after intravenous thyrotrophin releasing hormone (TRH) in two groups of patients with destructive pituitary lesions. Group A patients, who had more extensive pituitary hormone deficiencies and biochemical evidence of hypothyroidism at the time of study, had significantly lower mean serum TSH concentrations than the group B patients who were biochemically euthyroid. Basal TSH was below the lowest value seen in a control group of normal subjects in 5 of the 8 group A patients. In all patients TSH increased significantly after injection of TRH; the peak values being significantly correlated with the basal. In contrast to recent studies, which have emphasised other mechanisms in the production of secondary hypothyroidism, our data suggest that inadequate production of immunoassayable TSH is a common cause of secondary hypothyroidism in patients with destructive pituitary disease. Little, if any, additional clinical information is to be gained by measurement of TSH after TRH stimulation in this circumstance.