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J. P. Manning, S. G. Carter and M. C. Butler


The influences of uterine traumatization, ovariectomy and hormone replacement therapy on decidual alkaline phosphatase were studied in pseudopregnant rats. The enzyme was also assayed in implantation sites of pregnant rats with unilateral section and ligation of the Fallopian tubes. In all pseudopregnant animals with traumatized uteri, intact or castrate receiving progesterone replacement, the enzyme activity was 12 times more active on day 8 of pseudopregnancy than the contralateral non-traumatized horn. The alkaline phosphatase reaction of day 8 pregnant rats demonstrated a similar response at the implantation site. No increased enzyme was elicited by pseudopregnant rats treated with 17β-oestradiol and/or progesterone or animals ovariectomized and traumatized on day 4 and given only oestrogen. Additionally, the changes in alkaline phosphatase from day 5 to 10 in the intact and hormone-treated, ovariectomized pseudopregnant rats with traumatized uteri were similar to those demonstrated by the intact pregnant animals, i. e., an increased reaction from day 5 to 8 and decreased activity from day 8 to 10. The data support the view that the rise in decidual alkaline phosphatase in pregnant or traumatized pseudopregnant animals is dependent on the combined effect of uterine irritation and a progesterone-conditioned endometrium.

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Hiralal G Maheshwari, Ian Rifkin, Joan Butler and Michael Norman

To investigate changes in the growth hormone binding protein (GH-BP) in renal disease, gel chromatography was used to separate free and bound hormone after incubation with 125I-GH, the results being expressed as a percentage of radioactive GH eluting in a high molecular weight (70–80 kD) peak. In 26 normal individuals, binding was 39.3±8.0%, while in 11 patients with renal disease who were off dialysis binding was reduced to 16.8±5.6%. Similarly, in 9 patients undergoing hemodialysis binding was reduced to 24.6±6.8%, in 8 patients undergoing chronic ambulatory peritoneal dialysis binding was reduced to 25.7±7.6%, and in 9 patients within three months of a renal transplant binding was reduced to 25.1±8.6%. Scatchard analysis showed that these changes were not a result of decreased affinity of GH-BP for GH, and receptor binding studies showed that uremic serum was not inhibiting binding. The decreased concentration of GH-BP may indicate decreased expression of the GH receptor in target tissues, and hence diminished responsiveness to GH in renal failure.

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M. J. McMahon, A. V. J. Butler and G. H. Thomas


Slices of human benign prostatic hyperplasia were maintained in organ culture in the presence of [3H]- or [14C]testosterone.

Explants concentrated radioactivity from the culture medium, although this effect was depressed by the inclusion of foetal calf serum in the medium.

Testosterone was metabolised to products with chromatographic mobilities corresponding to androstanediols, androsterone, dehydroepiandrosterone, and androstanedione. The principal metabolite was identified as 5α-dihydrotestosterone, and small amounts of testosterone and androstenedione were also found.

As culture time increased from 1 to 6 days there was a diminution in the proportion of 5α-, and an increase in 17-ketometabolites, indicating a swing to a less physiological pattern of testosterone metabolism by the aging culture. Testosterone metabolism was thought to provide a sensitive index by which to evaluate changes in culture conditions.

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E. G. Lever, J. Butler, P. Moore, T. C. S. Cox and J. J. Maccabe

Abstract. Pituitary infarction occurring immediately after TRH injection (200 μg) is reported in a patient with gigantism due to a growth hormone-secreting pituitary macroadenoma. Evidence of infarction was seen in CSF and in serial CT scans. Regression of symptoms and sign of acromegaly, abolition of abnormal growth hormone secretion, and virtually complete anterior and partial posterior pituitary failure rapidly followed. The infarction was probably initiated by a hypertensive response to TRH. TRH testing in acromegalic subjects may require smaller doses of TRH to avoid unwanted pressor responses.

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W. R. Butler, L. C. Krey, K.-H. Lu, J. Espinosa-Campos, G. Weiss and E. Knobil

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Tamara Hew-Butler, Timothy D Noakes, Steven J Soldin and Joseph G Verbalis

Maintenance of fluid homeostasis during periods of heightened physical stress can be best evaluated in humans using exercise as a model. Although it is well established that arginine vasopressin (AVP), aldosterone and atrial natriuretic peptide (ANP) are the principle hormones regulating fluid balance at rest, the potential contributions of other related endocrine factors, such as oxytocin (OT) and brain natriuretic peptide (BNP), have not been well described during exercise. Seven endurance-trained runners completed three separate running trials: a maximal test to exhaustion (high intensity), a 60-min treadmill run (steady state), and a 56 km ultramarathon (prolonged endurance exercise). Statistically significant pre- to post-run increases were found only following the ultramarathon in [AVP]p (1.9 vs 6.7 pg/ml; P<0.05), [OT]p (1.5 vs 3.5 pg/ml; P<0.05), [NT-proBNP]p (23.6 vs 117.9 pg/ml; P<0.01), [interleukin 6]p (4.0 vs 59.6 pg/ml; P<0.05), [cortisol]p (14.6 vs 32.6 μg/ml; P<0.01), [corticosterone]p (652.8 vs 3491.4 ng/ml; P<0.05) and [11-deoxycortisol]p (0.1 vs 0.5 μg/ml; P<0.05) while a significant post-run increase in [aldosterone]p was documented after high-intensity (4.9 vs 12.5 ng/ml; P<0.05), steady-state (6.1 vs 16.9 ng/ml; P<0.05) and prolonged endurance running (2.6 vs 19.7 ng/ml; P<0.05). Similarly, changes in fluid balance parameters were significantly different between the ultramarathon versus high-intensity and steady-state running with regard to plasma volume contraction (less % contraction), body weight loss (increased % weight loss), plasma [Na+] Δ (decreased from baseline), and urine osmolality Δ (increase from baseline). Hypothetically driven relationships between [OT]p and [AVP]p (r=0.69; P<0.01) and between [NT-proBNP]p Δ and plasma [Na+] Δ (r=−0.79; P<0.001) – combined with the significant and unexpected pre- to post-race increases after prolonged endurance exercise – allows for possible speculation that OT and BNP may assist their better known companion hormones (AVP and ANP) in the regulation of fluid balance during conditions of extreme physical stress.

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U Das, AJ Whatmore, J Khosravi, JK Wales, G Butler, MS Kibirige, A Diamandi, J Jones, L Patel, CM Hall, DA Price and PE Clayton

BACKGROUND/AIM: In childhood an appropriate response to GH treatment is achieved by titration of growth response against dose administered, with careful observation for side-effects. In order to evaluate the potential use of IGF monitoring in children treated with GH, a cross-sectional study has been carried in 215 children and adolescents (134 with GH deficiency (GHD), 54 with Turner syndrome (TS) and 27 with non-GHD growth disorders) treated with GH for 0.2-13.7 years. METHODS: IGF-I and IGF-binding protein-3 (IGFBP-3) were measured in ELISAs, using dried capillary blood collected onto filter papers. Results were expressed as the mean S.D. range (SDS). Values of either analyte < -2 or > +2 SDS were considered abnormal. RESULTS: IGF-I and IGFBP-3 SDS were higher in the TS and non-GHD groups (mean +0.01 and +0.1 respectively) than in those with GHD (mean value -0.6). Nineteen per cent of the IGF-I values (13% low, 6% high) and 12% of IGFBP-3 values were abnormal (10% low, 2% high). Abnormalities, either low or high, were most common in the GHD group. There was a weak but significant relationship between change in height SDS over the Year up to the time of sampling in the whole group and IGF-I SDS. Satisfactory growth performance (+0.5>change in height SDS> -0.5) was found in those with high (7.2%), normal (60%) and low (9.3%) IGF-I levels. Overall, it was estimated that 26% of the tests would indicate that an adjustment to GH dose (up in 18% and down in 8%) could be considered. CONCLUSIONS: From this cross-sectional study of IGF monitoring across a broad range of diagnoses and ages, it can be concluded that the majority of children on GH have normal levels of IGF-I and IGFBP-3, but 26% of tests could suggest that a change of GH dose should be considered. Regular monitoring of IGF-I and IGFBP-3 should be considered in any child on GH treatment.

Open access

D B Allen, P Backeljauw, M Bidlingmaier, B M K Biller, M Boguszewski, P Burman, G Butler, K Chihara, J Christiansen, S Cianfarani, P Clayton, D Clemmons, P Cohen, F Darendeliler, C Deal, D Dunger, E M Erfurth, J S Fuqua, A Grimberg, M Haymond, C Higham, K Ho, A R Hoffman, A Hokken-Koelega, G Johannsson, A Juul, J Kopchick, P Lee, M Pollak, S Radovick, L Robison, R Rosenfeld, R J Ross, L Savendahl, P Saenger, H Toft Sorensen, K Stochholm, C Strasburger, A Swerdlow and M Thorner

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.