• Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly.

      Higham, Claire E; Rowles, Susannah V; Russell-Jones, D; Umpleby, A M; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom. (2009-07)
      INTRODUCTION: Acromegaly is complicated by an increased incidence of diabetes mellitus caused by impaired insulin sensitivity and reduced beta-cell function. Pegvisomant blocks activity at GH receptors, normalizing IGF-I in over 90% of patients and improving insulin sensitivity. The mechanisms for this increase in insulin sensitivity are not fully determined. We used stable isotope techniques to investigate the effects of pegvisomant on glucose and lipid metabolism in acromegaly. METHODS: Five patients (age, 43 yr +/- sd) with active acromegaly were studied on two occasions: before pegvisomant and after 4 wk of pegvisomant (20 mg daily sc). (2)H(5)-glycerol was infused overnight to measure overnight and early morning (basal) glycerol production rate (Ra). The next morning (2)H(2)-glucose was infused for 2 h before and throughout a hyperinsulinemic euglycemic (1.5 mU/kg x min insulin) clamp to measure basal glucose Ra and insulin-stimulated peripheral glucose disposal (Rd). RESULTS: Mean IGF-I was significantly reduced after pegvisomant treatment (mean, 539 +/- 176 vs. 198 +/- 168 microg/ml; P = 0.001). The insulin sensitivity of endogenous glucose production was significantly increased after pegvisomant [mean glucose Ra *insulin, 118.5 +/- 28 vs. 69.2 +/- 22 micromol/kg x min *(mU/liter); P = 0.04]. No differences in glucose Rd were seen after pegvisomant. All patients showed a reduction in glycerol Ra adjusted for insulin [mean, 18.12 +/- 1.75 vs. 14.4 +/- 4.75 micromol/kg x min *(mU/liter); P = 0.08] and overnight FFA concentrations (mean area under the curve, 278 +/- 84 vs. 203 +/- 71; P < 0.05) after pegvisomant. CONCLUSION: Short-term administration of pegvisomant leads to a reduction in overnight endogenous glucose production, and this may be related to reduced levels of FFA.
    • Successful use of weekly pegvisomant administration in patients with acromegaly.

      Higham, Claire E; Thomas, J; Bidlingmaier, M; Drake, William M; Trainer, Peter J; C Higham, Endocrinology, Christie Hospital, Manchester, M20 4BX, United Kingdom. (2009-05-01)
      Context Clinical trials using 80 mg once-weekly pegvisomant in active acromegaly led to a 30% fall in serum IGF-I. Subsequent studies demonstrated that daily administration of up to 40 mg/day achieved an IGF-I within reference range in 97% of patients. Pegvisomant has a half-life of >70hrs suggesting weekly dosing may be possible but using higher doses than in the initial trials. Objective To determine the efficacy of weekly dosing of pegvisomant. Design A two-center, open-label prospective study in patients with acromegaly converted from a stable daily dose of pegvisomant (median dose 15 mg daily [range 10-20 mg od], IGF-I normal for 3 months prior to inclusion) to twice-weekly (week 0-16) followed by once-weekly (week 16-32) administration. Results Seven patients (4M, age 57+/-7 yrs, 6/7 prior trans-sphenoidal surgery, 7/7 prior radiotherapy) were recruited. Six patients completed the twice-weekly and five patients both the twice-weekly and once-weekly administration. Headaches led to 2 patient withdrawals at 0 + 24 weeks. Mean pre-dose serum IGF-I levels remained stable with the different administration regimens (IGF-I baseline 145+/-39 ng/ml, twice-weekly 124+/-39 ng/ml and once-weekly 127+/-22 ng/ml) and all values were within age adjusted IGF-I reference range. Pegvisomant dose was reduced in 2 patients and 5 opted to continue weekly administration at trial termination. Safety and QOL parameters remained stable. Conclusions Twice and once-weekly administration of pegvisomant is effective in controlling serum IGF-I levels in acromegaly and although not formally assessed, continuation of weekly dosing in 5 patients at study conclusion suggests patient preference for this regimen.
    • Failure of antibody response to polysaccharide antigen in treated panhypopituitary adults.

      Mukherjee, Annice; Helbert, M; Ryder, W David J; Borrow, R; Davis, Julian R E; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. annice.mukherjee@srht.nhs.uk (2009-05)
      Although pituitary hormones are known to affect immune function, treated hypopituitarism is not a recognized cause of immune deficiency in humans. We set out to assess integrity of baseline and stimulated immune function in severely hypopituitary adults. Twenty-one panhypopituitary adults (group 1), on stable pituitary replacement including growth hormone, and 12 healthy volunteers (group 2) were studied. Lymphocyte subsets, pneumococcal antibody levels pre- and 1 month after polysaccharide vaccination, T cell numbers and in-vitro interferon (IFN)-gamma response were studied. There were no significant differences in T cell numbers or IFN-gamma secretion. B cell numbers were lower in group 1, especially those with low prolactin levels. Independent of this finding, nine of 21 patients in this group had low antibody response to polysaccharide antigen. This was most striking in those with low insulin-like growth factor 1 levels and appeared to be independent of the use of anti-convulsants or corticosteroid replacement. Significant humoral immune deficiency is seen in panhypopituitarism and may contribute to morbidity.
    • Mortality and serum insulin-like growth factor (IGF)-I and IGF binding protein 3 concentrations.

      Friedrich, Nele; Haring, Robin; Nauck, Matthias; Lüdemann, Jan; Rosskopf, Dieter; Spilcke-Liss, Elisabeth; Felix, Stephan B; Dörr, Marcus; Brabant, Georg E; Völzke, Henry; et al. (2009-05)
      BACKGROUND: Previous studies provided conflicting results regarding the association of serum IGF-I or IGF-binding protein-3 (IGFBP-3) and mortality. The aim of this study was to assess the relation of IGF-I and IGFBP-3 levels with mortality from all causes, cardiovascular disease (CVD), and cancer in a prospective population-based study. METHODS: From the Study of Health in Pomerania (SHIP) 1988 men and 2069 women aged 20-79 yr were followed up on average 8.5 yr. Causes of deaths were coded according to the International Classification of Diseases, 10th revision. Serum IGF-I and IGFBP-3 levels were determined by chemiluminescence immunoassays and categorized into three groups (low, normal, high) according to the sex- and age-specific 10th and 90th percentiles. RESULTS: Adjusted analyses revealed that men with low but not high IGF-I levels had an almost 2-fold higher risk of all-cause mortality [hazard ratio (HR) 1.92 (95% confidence interval [CI] 1.35; 2.73)], CVD mortality [HR 1.92 (95% CI 1.00; 3.71)], and cancer mortality [HR 1.85 (95% CI 1.00; 3.45)] compared with men with normal IGF-I levels. In women, no association between IGF-I and mortality was found. Moreover, low IGFBP-3 levels were associated with higher all-cause mortality in men [HR 1.87 (95% CI 1.31; 2.64)] and women [HR 1.63 (95% CI 0.96; 2.76)]. CONCLUSIONS: The present study found inverse associations between IGF-I or IGFBP-3 levels and mortality from all causes, CVD, or cancer in men and between IGFBP-3 and all-cause mortality in women.
    • A subnormal peak cortisol response to stimulation testing does not predict a subnormal cortisol production rate.

      Paisley, Angela N; Rowles, Susannah V; Brandon, D; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom. (2009-05)
      INTRODUCTION: The decision to commence lifelong glucocorticoid replacement therapy is often based on a cortisol stimulation test. We investigated the relationship between the peak cortisol response to insulin-induced hypoglycemia and daily cortisol production rate (CPR) to ascertain whether provocative tests are accurate in indicating the need to initiate lifelong glucocorticoid replacement. PATIENTS AND METHODS: Ten patients (five male; mean age, 44 +/- 13 yr) with pituitary disease and with demonstrably suboptimal peak cortisol response (350-500 nmol/liter) to insulin-induced hypoglycemia, underwent CPR measurement by isotope dilution using gas chromatography-mass spectrometry and 24-h urinary free cortisol (UFC). RESULTS: The median baseline and peak cortisol attained with hypoglycemia were 284 (164-323) and 473.5 (366-494) nmol/liter, respectively. A strong positive correlation was seen between peak stimulated cortisol and CPR (adjusted for body surface area) (r = 0.75; P = 0.02), and in all patients CPR [4.6 (2.9-15.1) mg/d x m(2)] was within the reference range (2.1-12 mg/d x m(2)) or elevated (one patient). A wide range was found for 24-h UFC [116.5 (20.5-265.9) nmol/liter] in this group of patients, and this parameter lacked significant correlation with either serum cortisol concentration or CPR. CONCLUSION: This is the first study to demonstrate a significant correlation between CPR and peak cortisol values during hypoglycemic challenge. An inadequate cortisol response to hypoglycemia suggests the need for glucocorticoid cover at times of stress, but these data indicate that a suboptimal peak cortisol does not equate to a low CPR and should not be an automatic indication for lifelong glucocorticoid replacement therapy. UFC bears no relation to serum cortisol or CPR and is therefore unhelpful in assessment of such patients.
    • Normal testicular function and spermatogenesis.

      Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, England, UK. (2009-04-02)
      The testis performs two basic functions, sperm production and testosterone secretion. Formation of the testis is genetically controlled; expression of the SRY gene directs the embryonic gonads into the pathway leading to the development of testes. By the fourth week of gestation in humans, the primordial germ cells derived from pluripotent cells of the embryonic epiblast proliferate and migrate from the endoderm of the yolk sac into the undifferentiated gonad, which becomes morphologically distinct during the seventh week of gestation in humans. Histological development of the testis is largely completed by the end of the third month of gestation. Pediatr Blood Cancer (c) 2009 Wiley-Liss, Inc.
    • Measurement of salivary cortisol with liquid chromatography-tandem mass spectrometry in patients undergoing dynamic endocrine testing.

      Perogamvros, Ilias; Owen, Laura J; Keevil, Brian G; Brabant, Georg E; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-03-19)
      Objective: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) eliminates cross-reactivity, which is a major limitation of immunoassays used for the measurement of salivary cortisol (SalC). We aimed to evaluate the potential of SalC measured by LC-MS/MS in patients undergoing assessment of the HPA axis. Design and patients: Cross-sectional study of 78 patients admitted for routine testing in a specialized endocrine unit. Measurements: Matched serum and saliva samples were collected from 68 patients who had a Short Synacthen Test (SST, 250 mcg IM) and 10 patients who had an Insulin Tolerance Test (ITT, insulin 0.15 U/kg IV). Serum cortisol (SerC) was measured with an automated immunoassay and SalC with LC-MS/MS. Adequate SerC responses were >500 nmol/l. Results: In all patients with adequate responses the relative increase in SalC was significantly higher than in SerC [6.4(0.3-26.1) vs 1.0(0.3-4.9), P<0.0001)]. The SerC-SalC relationship was better explained by an exponential rather than a linear model (R(2)=0.83 vs R(2)=0.65, both P<0.0001). Based on 59 patients with adequate SerC responses to an SST, an adequate SalC response was defined as 8.3 nmol/l. 7 patients following an SST and 3 patients following an ITT showed inadequate responses in both SerC and SalC, but two patients with CBG deficiency showed a low SerC with normal SalC. Conclusions: We have shown an excellent diagnostic sensitivity and specificity of LC-MS/MS SalC in the assessment of the HPA axis and superiority over SerC when CBG levels are altered. The exponential relationship between SerC and SalC supports the concept of CBG binding capacity saturation.
    • Use of a GH receptor antagonist (GHRA) to explore the relationship between GH and IGF-I in adults with severe GH deficiency (GHD).

      Berg, C A; Pokrajac, Ana; Bidlingmaier, M; Strasburger, Christian J; Shalet, Stephen M; Trainer, Peter J; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-03)
      OBJECTIVE: At diagnosis, approximately 50% of adults with severe GH deficiency (GHD) have an IGF-I within the reference range. It is unclear whether in such patients serum IGF-I levels are regulated by factors other than GH. DESIGN AND PATIENTS: We performed a double-blind, randomized, placebo-controlled, cross-over study to investigate the effect of the GH receptor antagonist - pegvisomant (20 mg daily for 14 days) on GH and IGF-I levels in three cohorts: patients with GHD and a normal IGF-I (NORMS); patients with GHD and a low IGF-I (LOWS) and healthy volunteers (CONS). RESULTS: Pegvisomant decreased IGF-I in CONS and NORMS [158.5 (101-206) vs. 103 (77-125) microg/l, P < 0.01; 124 (81-136) vs. 95 (51-113) microg/l, P < 0.01 respectively], but not in LOWS [31 (< 31-32) vs. 34.5 (< 31-38) microg/l], and this was associated with an increase in mean 24 h GH in CONS [0.49 (0.12-0.89) to 1.38 (0.22-2.45) microg/l (P = 0.03)] and in NORMS [69 (0-320)% from 0.1 (< 0.1-0.13) to 0.17 (0.11-0.42) microg/l (P = 0.03)], but not in the LOWS. The peak GH response to arginine was increased by pegvisomant in CONS and NORMS [6.1 (0.8-9) vs. 20.4 (13.1-28.8) microg/l, P = 0.03; 0.4 (0.1-0.5) vs. 0.5 (0.3-0.6) microg/l, respectively], but not in LOWS. CONCLUSIONS: These data indicate that patients with severe GHD with a normal IGF-I are able to increase GH secretion in response to a pegvisomant-induced fall in IGF-I, whereas those with low IGF-I levels are unable to increase GH secretion. Therefore circulating IGF-I appears to be GH-independent in GHD patients with a low IGF-I, but remains partially GH-dependent in GHD patients with a normal IGF-I.
    • The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index.

      Jostel, Andreas; Ryder, W David J; Shalet, Stephen M; Christie Hospital, Department of Endocrinology, Manchester, United Kingdom. (2009-02-18)
      SUMMARY Background: TSH secretion in hypopituitary patients may be decreased due to TSH deficiency, but it remains also under feedback inhibition by fT4. We propose a TSH Index (TSHI) as 'fT4-adjusted TSH', that corrects for any physiological TSH suppression, in order to provide a true estimate of pituitary thyrotrope function and any pathological pituitary suppression. Methods: 9519 TFTs (Bayer Immuno-1(R)) in 4064 patients of our institution were examined, including 444 patients investigated for hypopituitarism. Based on the physiological log-linear relationship between fT4 and TSH, we estimated the amount of feedback-induced change in logTSH per change in fT4, which allowed the extrapolation of logTSH to a fixed fT4 of 0, defining the TSH Index. TSH Indices were compared with other measures of pituitary function. Results: Feedback inhibition was estimated to cause a 0.1345 decrease in logTSH[mU/L] per 1pmol/L increase in fT4 concentration, i.e. TSHI=logTSH+0.1345xfT4. Patients with lower peak stimulated GH and cortisol concentrations had significantly lower TSHI (p<0.0001). TSH Indices measured before pituitary stimulation tests predicted highly significantly the risk of test failure (p=0.0002). 21.9% of all potential fT4-TSH combinations within the current reference ranges were identified as abnormal on the basis of the TSHI. Conclusion: The TSH Index provides an accurate estimate of the severity of pituitary dysfunction in hypopituitary patients based on simple TFTs. It predicts the probability of pituitary stimulation test failure, and extends the diagnosis of TSH deficiency into areas of the normal TFT reference ranges.
    • Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency).

      Darzy, Ken H; Thorner, Michael O; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. (2009-02)
      CONTEXT: We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic-pituitary (h-p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST. STUDY SUBJECTS AND DESIGN: We studied 24-h spontaneous GH secretion by 20-min sampling both in the fed state (n = 11) and in the last 24 h of a 33-h fast (n = 9) in adult cancer survivors with subnormal peak GH responses to the ITT but either normal or relatively less attenuated peak GH responses to the GHRH + AST. The study was conducted 8.3 +/- 1.8 (range 2-23) years after cranial irradiation for nonpituitary brain tumours (n = 9) or leukaemia/lymphoma (n = 2) in comparison with 30 normal controls (fasting, 14). RESULTS: Previously published diagnostic thresholds for the ITT, GHRH + AST and spontaneous GH secretion were used to characterize GH secretion. Four of the 11 patients with impaired stimulated responses to both tests showed only minor discordancies between stimulated and spontaneous GH secretion. Two of the remaining seven patients had subnormal spontaneous GH secretion. However, spontaneous GH secretion, both individually and as a group, was entirely normal in the remaining five patients who had impaired GH responses to the ITT but normal individual responses to the GHRH + AST; in these five patients, IGF-I standard deviation scores (SDS; -2.7 to -0.8) were significantly reduced to a moderate degree compared with normals. CONCLUSIONS: In cranially irradiated adult cancer survivors, it cannot be assumed that failure to pass the ITT in isolation reflects severe GH deficiency (GHD). It appears that in some patients near-maximal compensatory overdrive of the partially damaged somatotroph axis may result in near-normal quantitative restoration of spontaneous GH secretion, thus limiting further stimulation with the ITT to the extent that impaired GH responses can be seen even before spontaneous GH secretion starts to decline in adults. However, IGF-I status continues to provide useful information about the adequacy of the compensatory process and therefore the degree of normality of GH secretion.
    • GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset.

      Columb, Breeda; Smethurst, Linda E; Mukherjee, Annice; Jostel, Andreas; Shalet, Stephen M; Murray, Robert D; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (2009-02)
      BACKGROUND: Females secrete 2-3 -fold greater amounts of GH compared with males despite maintaining similar IGF-I levels. IGF-I generation tests in healthy subjects suggest this discordancy results from relative resistance to GH in females. In GHD females the presumed relative insensitivity to GH is reflected by a lower basal IGF-I and the need for higher GH maintenance doses during replacement. Adults with severe GHD of childhood-onset (CO) have lower basal IGF-I SDS and require higher GH maintenance doses compared with adult-onset (AO) patients with GHD of equal severity. We hypothesised CO-GHD adults to be less sensitive to GH than AO-GHD patients. METHODOLOGY: In a single site study we analysed the incremental change in IGF-I (DeltaIGF-I) in 116 GHD adults following initiation of GH replacement. The data were corrected to provide DeltaIGF-I/mg GH because of slight variances in initial GH dose. RESULTS: Following GH replacement DeltaIGF-I was 230 +/- 245 and 356 +/- 278 ng/ml/mg GH in females and males, respectively (P = 0.01). In CO and AO patients DeltaIGF-I was 282 +/- 206 and 294 +/- 292 ng/ml/mg GH, respectively (P = 0.83). Further analysis after stratification by both gender and timing of onset of GHD showed DeltaIGF-I was 226 +/- 164, 324 +/- 228, 231 +/- 268, and 373 +/- 304 ng/ml/mg GH in the CO females, CO males, AO females, and AO males, respectively (AO males vs. AO females, P = 0.03; CO males vs. CO females, P = 0.17; AO males vs. CO males, P > 0.05; AO females vs. CO females, P > 0.05). Multiple linear regression with DeltaIGF-I as the dependent variable and age, gender, BMI, baseline IGF-I level, and timing of onset as independent variables showed DeltaIGF-I to be dependent on gender alone (R = 0.28, P = 0.004). Age (P = 0.44), BMI (P = 0.54), baseline IGF-I level (P = 0.63) and timing of onset (P = 0.61) had no effect on DeltaIGF-I. CONCLUSION: We have shown gender to have a significant impact on GH sensitivity in GHD adults, which, at least in part, explains differences in maintenance dosages during replacement. None of the additional variables impacted significantly on GH sensitivity. The lower basal IGF-I SDS and higher GH replacement requirement reported in CO compared with AO patients cannot be explained by differences in sensitivity to GH.
    • Small vessel remodeling and impaired endothelial-dependent dilatation in subcutaneous resistance arteries from patients with acromegaly.

      Paisley, Angela N; Izzard, A S; Gemmell, I; Cruickshank, K; Trainer, Peter J; Heagerty, A M; Department of Endocrinology, Christie Hospital, Manchester, UK; Department of Cardiovascular Medicine, Manchester Royal Infirmary, Manchester, UK; National Primary Care Research and Development Centre, University of Manchester, UK. (2009-01-27)
      Context: Patients with acromegaly have increased morbidity and mortality, predominantly from cardiovascular disease. Hypertension and diabetes are more prevalent, both of which cause small vessel remodeling and endothelial dysfunction. Objective: To understand the structure and function of small arteries in acromegaly, subcutaneous blood vessels from gluteal fat biopsies were harvested from 18 patients with active disease (AD:56+/-15y, 14m), 23 in remission (CD:55+/-12y, 15m) and 20 healthy controls (55+/-11yrs, 10m) and examined in-vitro using pressure myography. Design: Contractile responses to cumulative noradrenaline concentrations were recorded followed by dose dependent dilator responses to acetylcholine. The acetylcholine protocol was repeated after incubation with a nitric oxide synthase inhibitor (L-NAME) and cyclooxygenase inhibitor (indomethacin). Following perfusion with Ca(2+)-free physiological saline solution, structural measurements were recorded at varying intraluminal pressures (3-180mmHg). Results: Wall thickness and wall:lumen ratio were increased in AD, reduced with treatment but remained greater in CD than controls. Wall cross-sectional area was increased in AD versus controls (P<0.001), decreased with treatment (AD vs CD: P<0.001) but remained higher than controls (CD vs controls: P=0.015). Growth index was increased in AD (20%) compared to controls (CD 9%). Contractility was similar in all groups. Endothelial-dependent dysfunction was evident in AD compared with CD (P<0.001) and controls (P<0.01). Dilation did not change following L-NAME but was impaired after indomethacin incubation. Conclusion: Active acromegaly is associated with hypertrophic remodeling of the vascular wall and embarrassed endothelial function due to reduced NO and EDHF bioavailability, both of which may contribute to the early mortality from cardiovascular disease.
    • Effect of aromatizable and unaromatizable androgen replacement in hypogonadal men on GH responsiveness.

      Gleeson, Helena K; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Wilmslow Road, Withington, Manchester, M20 4BX, UK. helena@kgleeson99.freeserve.co.uk (2009-01)
      OBJECTIVES: Although studies have clearly demonstrated that oestrogen replacement affects GH responsiveness by causing relative GH resistance, the effect of androgen replacement is unknown. Circumstantial evidence only suggests that androgen replacement may increase GH sensitivity and/or responsiveness. To examine the impact of androgens on GH responsiveness, hypogonadal men underwent the IGF-1 generation test in the unreplaced state, replaced with testosterone (T) and also replaced with dihydrotestosterone (DHT), its nonaromatizable metabolite. DESIGN AND PATIENTS: Twelve hypogonadal men with a normal GH axis were recruited. Each subject in random order had 4 weeks off T (NoRx), 4 weeks on T gel (TG) and 4 weeks on DHT gel (DHTG) applied daily, with 1 week washout between each preparation. An IGF-1 generation test using a subcutaneous injection of 7 mg of GH was performed at the end of each of these 4-week phases. MEASUREMENTS: Serum GHBP, total and free IGF-1, IGFBP-3 and acid-labile subunit (ALS) levels were measured at baseline and 24 h (peak) after GH administration. RESULTS: Despite a decrease in GHBP during the TG and DHTG phases, there were no observed differences in baseline, peak or increment (peak - baseline) total or free IGF-1 between the NoRx, TG or DHTG phases. CONCLUSIONS: There is no evidence of fluctuation in GH responsiveness in hypogonadal men, untreated or replaced with T or DHT alone. This implies that the increased level of oestradiol as a consequence of T replacement in hypogonadal men does not impact significantly on GH responsiveness, nor is there evidence of an androgen effect with elevated DHT levels as a consequence of either T or DHT replacement.
    • Etiology, baseline characteristics, and biochemical diagnosis of GH deficiency in the adult: are there regional variations?

      Brabant, Georg E; Poll, E M; Jonsson, P; Polydorou, D; Kreitschmann-Andermahr, Ilonka; Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX. (2009)
    • Hypopituitarism following Radiotherapy Revisited.

      Darzy, Ken H; Shalet, Stephen M; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (2009)
      Neuroendocrine disturbances in anterior pituitary hormone secretion are common following radiation damage to the hypothalamic-pituitary (H-P) axis, the severity and frequency of which correlate with the total radiation dose delivered to the H-P axis and the length of follow-up. The somatotropic axis is the most vulnerable to radiation damage and GH deficiency remains the most frequently seen endocrinopathy. Compensatory hyperstimulation of a partially damaged somatotropic axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses in adults. At its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite the normality of spontaneous GH secretion. In children, failure of the hyper-stimulated partially damaged H-P axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the insulin tolerance test remains the gold standard for assessing H-P functional reserve. With low radiation doses (<30 Gy) GH deficiency usually occurs in isolation in about 30% of patients, while with radiation doses of 30-50 Gy, the incidence of GH deficiency can reach 50-100% and long-term gonadotropin, TSH and ACTH deficiencies occur in 20-30, 3-9 and 3-6% of patients, respectively. With higher dose cranial irradiation (>60 Gy) or following conventional irradiation for pituitary tumours (30-50 Gy), multiple hormonal deficiencies occur in 30-60% after 10 years of follow-up. Precocious puberty can occur after radiation doses of <30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Hyperprolactinaemia, due to hypothalamic damage is mostly seen in young women after high dose cranial irradiation and is usually subclinical. H-P dysfunction is progressive and irreversible and can have an adverse impact on growth, body image, sexual function and quality of life. Regular testing is advised to ensure timely diagnosis and early hormone replacement therapy.
    • Pituitary-independent effect of octreotide on IGF-I generation.

      Pokrajac, Ana; Frystyk, Jan; Flyvbjerg, Allan; Trainer, Peter J; Department of Endocrinology, Christie NHS Foundation Trust, Manchester, M20 4BX, United Kingdom. (2009)
      Background: Somatostatin analogues (SSTAs) are frequently used for medical treatment of acromegaly. The rationale for their use is based on inhibition of pituitary GH secretion; however, there is in vitro evidence that octreotide also acts to inhibit hepatic IGF-I generation. Aim&Design: We studied the pituitary-independent effects of octreotide on IGF-I generation in 11 severely GH deficient humans (age 38, range 23-52; 7 male; BMI 24.7+/-3 kg/m2; peak stimulated GH <3mug/L; 3+/-1 pituitary hormone deficiencies) on a stable dose of GH replacement (0.4+/-0.1 mg) for at least 6 months. Patients were studied before and after 50 mug of subcutaneous octreotide three times a day for 7 days. Results: At study entry, all patients had total IGF-I within age- and gender-related reference range (SDS 0.4+/-1.0). Octreotide treatment resulted in a significant fall in total IGF-I (by 18%, 208+/-89 vs. 173+/-62 mug/L, P=0.04), free IGF-I (by 13%, 0.83+/-0.36 vs. 0.70+/-0.33 mug/L, P=0.01) and IGFBP-3 (6%, 4475+/-745 vs. 4209+/-912 mug/L, P=0.02). Octreotide suppressed fasting insulin from 8.1+/-3.4 to 6.3+/-4.1 mU/L (P=0.01) and was associated with a rise in fasting glucose from 5.2+/-0.9 to 5.8+/-0.9 mmol/L (P<0.01). IGFBP-1 increased by 84% from 42+/-26 to 95+/-52 mug/L (P=0.04). Conclusion: Our study demonstrates that octreotide induces a significant fall in IGF-I in severely GH deficient adults on fixed-dose of GH replacement. This is the evidence for a non-pituitary action of octreotide on the GH/IGF-I axis, most likely by antagonizing the action of GH on hepatic IGF-I generation and indirectly, by suppressing insulin secretion.
    • Altered phenotype of NK cells from obses rats can be normalized by transfer into lean animals.

      Lautenbach, Anne; Wrann, Christiane D; Jacob, Roland; Muller, Guenter; Brabant, Georg E; Nave, Heike; Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany. (2009)
    • Hypopituitarism following radiotherapy.

      Darzy, Ken H; Shalet, Stephen M; Diabetes and Endocrinology, East & North Hertfordshire NHS Trust, Howlands, Welwyn Garden City AL7 4HQ, UK. kendarzy@hotmail.com (2009)
      Deficiencies in anterior pituitary hormones secretion ranging from subtle to complete occur following radiation damage to the hypothalamic-pituitary (h-p) axis, the severity and frequency of which correlate with the total radiation dose delivered to the h-p axis and the length of follow up. Selective radiosensitivity of the neuroendocrine axes, with the GH axis being the most vulnerable, accounts for the high frequency of GH deficiency, which usually occurs in isolation following irradiation of the h-p axis with doses less than 30 Gy. With higher radiation doses (30-50 Gy), however, the frequency of GH insufficiency substantially increases and can be as high as 50-100%. Compensatory hyperstimulation of a partially damaged h-p axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses; at its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite normality of spontaneous GH secretion in adults. In children, failure of the hyperstimulated partially damaged h-p axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the ITT remains the gold standard for assessing h-p functional reserve. Thyroid-stimulating hormone (TSH) and ACTH deficiency occur after intensive irradiation only (>50 Gy) with a long-term cumulative frequency of 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose less than 30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia, due to hypothalamic damage leading to reduced dopamine release, has been described in both sexes and all ages but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies (30-60% after 10 years) occur after more intensive irradiation (>60 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. The frequency of hypopituitarism following stereotactic radiotherapy for pituitary tumors is mostly seen after long-term follow up and is similar to that following conventional irradiation. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy.
    • Topiramate can induce hypoadrenalism in patients taking oral corticosteroid replacement.

      Jacob, K; Trainer, Peter J; Department of Endocrinology, Christie Hospital NHS Trust, Manchester M20 4BX. drkoshyjacob@gmail.com (2009)
    • ACTROSTUDY: the first 5 years

      Trainer, Peter J; Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK (2009)