Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly

Background  An essential criterion for control of acromegaly is normalization of IGF-I levels. Somatostatin analogues act to suppress IGF-I and GH levels.
Objective  To assess the efficacy and safety of 48 weeks titrated dosing of lanreotide Autogel.
Design  Open-label, multicentre, phase III, 48-week trial.
Methods  Patients with active acromegaly (IGF-I levels > 1·3 times upper limit of age-adjusted normal range) were recruited. Twelve injections of lanreotide Autogel were given at 28-day intervals: during the 16-week fixed-dose phase, patients received 90 mg; in the 32-week dose-titration phase, patients received 60, 90 or 120 mg according to GH and IGF-I levels. Intention-to-treat analysis was performed to determine the proportion of patients with normalized age-adjusted IGF-I levels at study end. Secondary evaluations included GH levels, clinical acromegaly signs and safety.
Results  Fifty-seven of 63 patients completed the study. Lanreotide Autogel resulted in normalized age-adjusted IGF-I levels in 27 patients (43%, 95% CI 31–55). Mean GH levels decreased from 6·2 to 1·5 µg/l at study end, with 53 of 62 patients (85%) having GH levels ≤ 2·5 µg/l (95% CI 76·7–94·3) and 28 of 62 patients (45%) with levels < 1 µg/l (95% CI 32·8–57·6). Twenty-four (38%) had both normal IGF-I levels and GH levels ≤ 2·5 µg/l. Acromegaly symptoms reduced significantly in most patients throughout the study. The most common adverse events were gastrointestinal, as expected for somatostatin analogues.
Conclusions  Using IGF-I as primary end-point, 48 weeks lanreotide Autogel treatment, titrated for optimal hormonal control, controlled IGF-I and GH levels effectively, reduced acromegaly symptoms and was well tolerated.     

Spinal volumetric trabecular bone mass in acromegalic patients: a longitudinal study

Objective  Data on trabecular bone mass in acromegaly are controversial. All the studies are cross-sectional and bone mineral density (BMD) has been evaluated largely by dual X-ray absorptiometry (DXA), which is influenced by bone enlargement. In this study we assessed in acromegalic patients the effects overtime of GH excess on trabecular bone mass measured by single-energy quantitative computed tomography (QCT) which is not influenced by bone size.
Design  Longitudinal retrospective study.
Patients  A total of 46 acromegalic patients followed-up for 48 months (median), subdivided into four groups: group A (eugonadal patients with active disease: n  = 13), group B (hypogonadal patients with active disease; n  = 9), group C (eugonadal patients with controlled disease; n  = 10), group D (hypogonadal patients with controlled disease; n  = 14).
Measurements  Serum GH and IGF-I levels, spinal trabecular BMD, and vertebral fractures were evaluated in all patients. BMD variations were reported as change (Δ) in Z -values (Z-QCT) measured at baseline and end of follow-up per year (Δ Z-QCT).
Results  Δ Z-QCT was greater in group A vs. group B and D ( P = 0·002 and P  = 0·0001, respectively) and in group C vs. group D ( P = 0·009). Multivariate regression analysis showed that hypogonadal status (β = –0·69; P  = 0·001) and baseline duration of hypogonadism (β = 0·44; P  = 0·02) but not baseline duration of acromegaly, length of follow-up and disease activity, were significantly associated with Δ Z-QCT.
Conclusions  This longitudinal study suggests that the effect of chronic GH excess on spinal trabecular bone mass seems to be anabolic in active eugonadal patients but not in hypogonadal ones.     

Factors determining inadequate hypoglycaemia during insulin tolerance testing (ITT) after pituitary surgery

Background  Some patients fail to achieve adequate hypoglycaemia following a standard dose of intravenous insulin during the insulin tolerance test (ITT). Persistent acromegaly or Cushing's disease may contribute to inadequate hypoglycaemia.
Aim  To identify factors that predict failure to achieve adequate hypoglycaemia during an ITT after pituitary surgery.
Methods  We reviewed consecutive ITTs performed over a 10-year period in 76 patients following pituitary surgery. Analyses were performed to determine if body mass index (BMI), fasting blood glucose (FBG), cortisol, GH status or underlying diagnosis influenced the outcome.
Results  Adequate hypoglycaemia (blood glucose < 2·2 mmol/l) was not achieved in 33 patients (Group 1) following a standard dose of neutral insulin (0·1 units/kg); 43 patients (Group 2) achieved adequate hypoglycaemia. Group 1 had significantly higher BMI, FBG, baseline cortisol and peak cortisol concentrations than Group 2. Peak GH response was not different. Multiple regression analysis showed that FBG was the only independent predictor of adequate hypoglycaemia. An insulin dose of 0·2 units/kg achieved adequate hypoglycaemia in 80% of patients with FBG ≥ 5·5 mmol/l. In patients with acromegaly or Cushing's disease, failure to achieve adequate hypoglycaemia was associated with persistent disease.
Conclusion  FBG is an important determinant of the dose of insulin required to achieve adequate hypoglycaemia during an ITT in patients after pituitary surgery. A standard insulin dose of 0·1 U/kg is insufficient for adequate hypoglycaemia in patients with FBG > 5·5 mmol/l. Adequate response to a standard dose of insulin suggests a likelihood of cure of acromegaly or Cushing's disease after pituitary surgery.     

Serum IGF-I measured by four different immunoassays in patients with adult GH deficiency or acromegaly and in a control population

Background  IGF-I is a useful tool in GH disorders diagnosis, however, the use of commercially available kits needs to be validated.
Objective  To validate the use of serum IGF-I concentrations measured by four immunoassays in the diagnosis of adult GH deficiency and acromegaly.
Design  Cross-sectional study.
Patients  Fifty GH-deficient (GHD) patients, 41 acromegaly patients and 405 controls.
Measurements  Serum IGF-I concentrations were measured by four commercial immunoassays: (1) RIA-NICHOLS; (2) ICMA-IMMULITE; (3) IRMA-IMMUNOTECH; and (4) non-extraction-IRMA-DSL. Reference values were established from the control population in six age groups. Individual results were transformed to standard deviation score (SD score) from the age-related reference population and reference data provided by each assay manufacturer. Diagnostic sensitivity for GH deficiency was calculated.
Results  IGF-I measured by the four assays differed significantly. In controls, assay 2 yielded the lowest results, followed by assays 1, 3 and 4 ( P <  0·0001 for all comparisons). IGF-I declined with age, but no sex-related differences were observed. When IGF-I was standardized with respect to reference data obtained from the manufacturers, it showed better sensitivity in assays 1 and 2, than with our controls (65% vs. 77·5% and 58% vs. 70%, respectively) for GHD diagnosis. With assays 3 and 4, higher sensitivity was obtained when standardized with our controls (62% vs. 52% and 56% vs. 36%, respectively). In acromegaly, IGF-I was > 2 SD score with all assays.
Conclusions  IGF-I SD score for GHD diagnosis differed according to the normative data used. All assays proved to be useful for active acromegaly diagnosis.     

Pegvisomant-primed GH stimulation test

Objective  Provocative stimulation tests for GH assessment have poor reproducibility and can often elicit false positive results in normal children. The aim of our study was to evaluate the capability of pegvisomant, as an enhancer of GH secretion, in unmasking false-positive results in short children undergoing GH testing.
Design  A prospective study was conducted between March 2005 and April 2006.
Patients  Twenty-one short children (8 males and 13 females), aged 1·0–14·5 years, with a height of < 2 SD scores below the mean were included in the study.
Methods  All subjects underwent an l -DOPA stimulation test with evaluation of GH. At the end of the test, 1 mg/kg of pegvisomant was given subcutaneously and 3 days later an l -DOPA stimulation test was repeated.
Results  There was a significant decrease of IGF-I SDS following pegvisomant (–1·75 ± 0·24 vs. –2·65 ± 0·23; P  < 0·0001) and a significant increase of the GH-peak (6·2 ± 0·91 vs. 15·3 ± 2·30 µg/l; P  < 0·0001). Among the 21 patients examined, 18 (85·7%) had an insufficient response (< 10 µg/l) at the first stimulation. Ten of them (55·5%) showed normal secretion after priming with pegvisomant, while insufficient secretory reserve was confirmed in the remaining eight.
Conclusions  Pegvisomant priming before GH stimulation tests can be used to improve the reliability of the diagnostic work up in GH deficiency. Further studies are required, however, to clarify whether this procedure should be recommended in the routine evaluation of GH status.     

High prevalence of biochemical acromegaly in primary care patients with elevated IGF-1 levels

Objective  The estimated prevalence of acromegaly is 40–125 per million. The diagnosis of acromegaly is often delayed due to deficits in recognizing the signs of the disease. It is not known how many subjects with increased IGF-1 levels have acromegaly. We aimed to assess the prevalence of acromegaly in primary care by screening for elevated IGF-1 levels.
Design  A cross-sectional, epidemiological study (the DETECT study).
Patients  A total of 6773 unselected adult primary care patients were included.
Measurements  We measured IGF-1 in all patients and recommended further endocrine evaluation in all patients with elevated IGF-1 levels (> 2 age-dependent SDS).
Results  Of 125 patients with elevated IGF-1 levels, 76 patients had indeterminate results and acromegaly could be excluded in 42 patients. One patient had known florid acromegaly. Two patients had newly diagnosed acromegaly and pituitary adenomas. Four patients had biochemical acromegaly but refused further diagnostics. This corresponds to a prevalence of 1034 per million patients.
Conclusions  Our study shows a high prevalence of undiagnosed acromegaly in primary care. These results imply that acromegaly is underdiagnosed and stress the importance of detecting acromegaly.     

Ultrasound of peripheral nerves in acromegaly: changes at 1-year follow-up

Context  We have previously demonstrated peripheral nerve enlargement in acromegaly.
Objective  The aim of this study was to use ultrasound (US) to assess any changes in the peripheral nerves of patients with acromegaly 1 year after the first evaluation.
Patients  We prospectively examined the median and ulnar nerve cross-sectional area (CSA) in 34 non-diabetic, patients with acromegaly (18 females and 16 males; 18–79 years) and 34 age-, sex-, BMI-matched controls, using a 17–5 MHz US probe.
Intervention  The median nerve was examined at the mid-forearm (MN-f) and at the carpal tunnel (MN-Ct) levels; the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a). Patients were grouped according to the clinical control of the disease: 'improved'; 'always controlled'; 'always uncontrolled'; and 'worsened'.
Results  The median nerve at mid-forearm (MN-f), the ulnar nerve at mid-forearm (UN-f) and at distal arm (UN-a) were significantly reduced after 1-year follow-up in all patients ( P <  0·001, P  < 0·008, P  < 0·012, respectively). In the 'improved' group, there was a significant reduction of median nerve CSA examined at mid-forearm (MN-f) ( P =  0·02), and distal arm ulnar nerve CSA (UN-a) ( P =  0·002). In the other groups no statistically significant differences in ultrasound parameters were recorded. However, UN-a, UN-f, MN-f, MN-ct were still significantly higher in all groups compared with controls ( P <  0·001).
Conclusion  These data demonstrate that median and ulnar nerves CSA are reduced after 1 year follow-up, in line with the reduction of GH/IGF-I levels. However, as the control of the disease incompletely reverts nerve enlargement, this phenomenon could be only partially reversible.     

Peroxisome proliferator-activated receptor gamma agonism modifies the effects of growth hormone on lipolysis and insulin sensitivity

Context  Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists such as thiazolidinediones (TZDs) improve insulin sensitivity in type 2 diabetes mellitus (T2DM) through effects on fat metabolism whereas GH stimulates lipolysis and induces insulin resistance.
Objective  To evaluate the impact of TZDs on fat metabolism and insulin sensitivity in subjects exposed to stable GH levels.
Design  A randomized, placebo-controlled, double-blind parallel-group study including 20 GH-deficient patients on continued GH replacement therapy. The patients were studied before and after 12 weeks.
Intervention  Patients received either pioglitazone 30 mg ( N  = 10) or placebo ( N  = 10) once daily for 12 weeks.
Results  Adiponectin levels almost doubled during pioglitazone treatment ( P =  0·0001). Pioglitazone significantly decreased basal free fatty acid (FFA) levels ( P =  0·02) and lipid oxidation ( P =  0·02). Basal glucose oxidation rate ( P =  0·004) and insulin sensitivity ( P =  0·03) improved in the patients who received pioglitazone treatment. The change in insulin-stimulated adiponectin level after pioglitazone treatment was positively correlated to the change in insulin-stimulated total glucose disposal ( R  = 0·69, P  = 0·04).
Conclusion  The impact of GH on lipolysis and insulin sensitivity can be modified by administration of TZDs.     

Effect of Sandostatin LAR on serum leptin levels in patients with acromegaly

Serum leptin levels are decreased in patients with acromegaly and rise after GH is normalized by surgical treatment. We have evaluated the effect of Sandostatin LAR on leptin levels in acromegalic patients since there are recent data to suggest that somatostatin, in addition to its GH lowering effect, also reduces serum leptin levels in humans. Nineteen patients with active acromegaly were studied. Eleven patients received monthly injection of Sandostatin LAR and eight patients underwent transsphenoidal surgery. Serum concentrations of leptin, GH, IGF-1 and insulin were measured before and after treatment. Serum leptin concentrations were lower in patients with active acromegaly than controls matched for age, sex and body mass index (BMI) [2.79 microg/l (2.60) vs. 4.41 microg/l (5.07); median (inter-quartile range); P < 0.01]. A positive correlation between serum leptin concentrations and BMI was observed in the controls (r = 0.46, P < 0.05) but not in the acromegalic patients before treatment (r = 0.32, ns). In the group of patients treated with Sandostatin LAR, a marked reduction in GH and IGF-1 was achieved by week 8 and GH and IGF-1 remained suppressed throughout the 6 months of treatment. There was no change in BMI. A significant increase in leptin levels only became evident after 6 months of treatment [2.99 microg/l (2.60) vs. 4.21 microg/l (3.84), P < 0.05]. Leptin levels also significantly increased after transsphenoidal surgery [3.05 microg/l (5.73) vs. 5.19 microg/l (4.93), P < 0.05]. The positive correlation between serum leptin concentrations and BMI was restored in acromegalic patients both after treatment with Sandostatin LAR (r = 0.62, P < 0.05) and after surgery (r = 0.81, P < 0.05). Leptin concentrations were decreased in patients with active acromegaly and lowering GH by either Sandostatin LAR or transsphenoidal surgery led to an increase in leptin concentrations.     

Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland

Objectives  The presence of an ectopic posterior pituitary gland (EPP) in childhood is associated with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency. GHD in late adolescence has been defined as a peak GH level <5 μg/l. The aim of this study was to identify the likelihood of persistent GHD in late adolescence in patients with an EPP compared with those with a normally sited posterior pituitary (NPP).
Methods  In 18 patients with an EPP and 15 patients with an NPP, clinical, biochemical and radiographic data were collected.
Results  In the EPP vs. the NPP group, the change in peak GH levels at the end of growth was less (+0·4[95% confidence interval (CI) - 0·8 to 2·7] vs. +4·1[95%CI + 0·4 to +10·5] μg/l, P -value for ancova  = 0·03, after adjustment for age and sex). Using a peak GH level of <5 μg/l as a cut-off for GHD, 66% of EPP subjects compared with 40% of NPP subjects had GHD ( P  = 0·3). Hundred per cent of EPP subjects had a peak GH level on retesting <10 μg/l, compared with 40% of NPP subjects ( P  < 0·001).
Conclusion  It is important to document GH status at the end of growth, even if there is a structural abnormality of the hypothalamic–pituitary axis. The presence of an EPP compared to an NPP increases the likelihood of persistent GHD by 26%. As all EPP patients had a peak GH level of <10 μg/l, the cut-off for persistent GHD in late adolescence may need to be revised.     

GH receptor d3 polymorphism in Dutch patients with MPHD and IGHD born small or appropriate for gestational age

Objective  GH acts through the GH receptor (GHR). The GHR gene contains a genetic polymorphism caused by a deletion of exon 3 ( d3 ), with high frequency in the normal population. There is a continuing controversy whether the presence or absence of the exon 3 deletion ( d3+ vs. d3– ) affects the effect of GH in human growth.
Design, patients and measurements  For 144 patients with idiopathic isolated GH deficiency (IGHD, n  = 72) or multiple pituitary hormone deficiency (MPHD, n  = 72), amplification of the region around exon 3 of the GHR gene was performed. Clinical data and response to GH treatment were compared between GHR d3+ and d3– IGHD and MPHD patients born either small for gestational age (SGA) or appropriate for gestational age (AGA).
Results  IGHD patients born SGA had a significantly higher d3+ frequency (82%) than IGHD patients born AGA (35%, P  = 0·006). Within the group of IGHD patients born SGA, d3 – patients showed a slightly better spontaneous catch up growth before start of GH treatment than d3 + patients (1·1 ± 1·1 SD vs. 0·6 ± 1·1 SDS, P  = 0·040) There was no difference in patients first year's response to GH treatment between GHR d3 + and d3– patients.
Conclusions  In IGHD and MPHD patients, response to GH treatment was independent of GHR genotype. GHR- d3 was significantly more frequent among IGHD patients born SGA. As we are the third to report an association between birth size and GHR d3 status, it is conceivable that the GHR- d3 might affect prenatal growth in IGHD patients by a yet unknown mechanism.     

Monitoring of acromegaly: what should be performed when GH and IGF‐1 levels are discrepant?

Monitoring of a patient with acromegaly requires periodic evaluation of levels of GH and IGF-1, the biochemical markers of this disease. Although the results of these two tests are usually concordant, they can be discrepant and how to proceed when they are can be a challenging clinical problem. In some cases, IGF-1 levels are normal yet GH suppression after oral glucose is abnormal; this pattern may be due to persistent GH dysregulation despite remission. In other cases, IGF-1 levels are elevated yet GH suppression appears to be normal; this pattern may be observed if the cutoff for GH suppression is inappropriately high for the GH assay being used. Various conditions known to alter GH and IGF-1 including malnutrition, thyroid disease and oestrogen use as well as the potential for methodological or normative data issues with the GH and IGF-1 assays should be considered in the interpretation of discrepant results. When a known cause of the discrepancy other than acromegaly is not identified, a clinical decision about the patient's therapy needs to be made. We adjust treatment in most patients whose results are discrepant based on the IGF-1 level, continuing current treatment if it is persistently normal or modifying this if it is elevated. The clinical picture of the patient, however, also needs to be incorporated into this decision. All patients should have continued periodic surveillance of both GH and IGF-1 levels.     

Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance?

Objective  The aetiology of idiopathic intracranial hypertension (IIH) is not known, but its association with obesity is well-recognized. Recent studies have linked obesity with abnormalities in circulating inflammatory and adiposity related cytokines. The aim of this study was to characterize adipokine and inflammatory cytokine profiles in IIH.
Design  Paired serum and cerebrospinal fluid (CSF) specimens were collected from 26 patients with IIH and compared to 62 control subjects. Samples were analysed for leptin, resistin, adiponectin, insulin, IL-1β, IL-6, IL-8 (CXCL8), TNFα, MCP-1 (CCL2), hepatocyte growth factor, nerve growth factor and PAI-1 using multiplex bead immunoassays.
Results  CSF leptin was significantly higher in patients with IIH ( P  = 0·001) compared to controls after correction for age, gender and body mass index (BMI). In the control population, BMI correlated with serum leptin ( r  = 0·34; P  = 0·007) and CSF leptin ( r  = 0·51; P  < 0·0001), but this was not the case for the IIH population. Profiles of other inflammatory cytokines and adipokines did not differ between IIH patients and controls once anthropometric factors had been accounted for.
Conclusions  IIH was characterized by significantly elevated CSF leptin levels which did not correlate with BMI. We suggest that CSF leptin may be important in the pathophysiology of IIH and that obesity in IIH may occur as a result of hypothalamic leptin resistance.     

Augmentation index in resistance to thyroid hormone (RTH)

Objective  Resistance to thyroid hormone (RTH) is associated with a varied clinical presentation. The cardiac effects of RTH have been described but vascular function has yet to be fully evaluated in this condition. We have measured the arterial function of those with RTH to assess any vascular changes.
Design  An observational study.
Patients  Twelve RTH patients were recruited from the thyroid clinic (mean value ± SD), age 40·8 ± 18·7 years; BMI 27·2 ± 4·2 kg/m² and compared with 12 healthy, euthyroid, age-matched controls (age 41·4 ± 19·3; BMI 24·8 ± 4·4 kg/m²) with no history of cardiovascular disease. No interventional measures were instituted.
Measurements  Arterial stiffness was measured using pulse wave analysis at the radial artery. Thyroid function, fasting lipids and glucose were also measured on the same occasion in both patients and controls.
Results  The corrected augmentation index, a surrogate marker of arterial stiffness was significantly higher in patients compared with controls (21·0% ± 14·1% vs. 5·4% ± 18·2%, P  < 0·03). Low density lipoprotein cholesterol (LDL-cholesterol) levels were also significantly elevated in patients compared with controls (3·0 ± 0·6 vs. 2·1 ± 0·5 mmol/l; P  < 0·002).
Conclusion  RTH patients show evidence in this study of increased augmentation index consistent with an increase in arterial stiffness compared with euthyroid controls. They also demonstrate elevated LDL-cholesterol levels. Both these measures may lead to increased cardiovascular risk.     

Consequences of lifetime isolated growth hormone (GH) deficiency and effects of short-term GH treatment on bone in adults with a mutation in the GHRH-receptor gene

Objective  Growth hormone (GH) influences bone mass maintenance. However, the consequences of lifetime isolated GH deficiency (IGHD) on bone are not well established. We assessed the bone status and the effect of 6 months of GH replacement in GH-naïve adults with IGHD due to a homozygous mutation of the GH-releasing hormone (GHRH)-receptor gene ( GHRHR ).
Patients and methods  We studied 20 individuals (10 men) with IGHD at baseline, after 6 months of depot GH treatment, and 6 and 12 months after discontinuation of GH. Quantitative ultrasound (QUS) of the heel was performed and serum osteocalcin (OC) and C-terminal cross-linking telopeptide of type I collagen (ICTP) were measured. QUS was also performed at baseline and 12 months later in a group of 20 normal control individuals (CO), who did not receive GH treatment.
Results  At baseline, the IGHD group had a lower T -score on QUS than CO (–1·15 ± 0·9 vs. –0·07 ± 0·9, P  < 0·001). GH treatment improved this parameter, with improvement persisting for 12 months post-treatment ( T -score for IGHD = –0·59 ± 0·9, P  < 0·05). GH also caused an increase in serum OC (baseline vs. pGH, P  < 0·001) and ICTP (baseline vs. pGH, P  < 0·01). The increase in OC was more marked during treatment and its reduction was slower after GH discontinuation than in ICTP.
Conclusions  These data suggest that lifetime severe IGHD is associated with significant reduction in QUS parameters, which are partially reversed by short-term depot GH treatment. The treatment induces a biochemical pattern of bone anabolism that persists for at least 6 months after treatment discontinuation.     

Initial growth deceleration during GnRH analogue therapy for precocious puberty

Objectives  To compare the efficacy of goserelin and leuprolide on initial deceleration of growth and weight gain during the first 12 months of GnRH analogue treatment for precocious puberty.
Design  Retrospective cohort analysis.
Patients  Forty children with precocious puberty treated with either goserelin or leuprolide (33 females, mean age 7·3 and 7·7 years, respectively, at the start of treatment).
Measurements  The primary outcomes were baseline-to-6-months and 6-months-to-12-months change in height standard deviation score (SDS) and body mass index (BMI). Relative tall stature was calculated as the difference between height SDS and mid-parental height (MPH) SDS at baseline.
Results  Goserelin and leuprolide were associated with similar suppression of serum LH during the first 12 months of treatment ( P =  0·62). Greater relative tall stature was strongly associated with more advanced bone age, greater BMI SDS and with greater reduction in height SDS in the first 6 months. Adjusted for relative tall stature, goserelin therapy was associated with significantly greater suppression of growth than leuprolide ( P =  0·025) in the first 6 months of treatment, with no subsequent change in the second 6 months. A similar, significant increase in BMI was seen with both analogues.
Conclusions  Both GnRH analogues were associated with effective biochemical suppression of puberty; however, goserelin was more effective at reducing linear growth during the first 6 months. Relative tall stature was a major determinant of the initial response to treatment.     

Peroxisome proliferator-activated receptor γ (PPAR) agonism reduces the insulin-stimulated increase in circulating interleukin-6 in GH replaced GH-deficient adults

Context  Peroxisome proliferator-activated receptor γ (PPARγ) agonists modify cardiovascular risk factors and inflammatory markers in patients with type 2 diabetes. GH treatment in GH-deficient (GHD) patients may cause insulin resistance and exerts ambiguous effects on inflammatory markers.
Objective  To investigate circulating markers of inflammation and endothelial function in GH replaced GHD patients before and after 12 weeks administration of either pioglitazone 30 mg/day ( N  = 10) or placebo ( N  = 10) in a randomized double-blind parallel design.
Methods  Circulating levels of interleukins (ILs)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, high sensitivity C-reactive protein, vascular cell adhesion molecule-I, and osteoprotegerin (OPG) were measured in the basal state and after a 2·5 h hyperinsulinaemic euglycaemic clamp.
Results  Insulin sensitivity improved in the group receiving PPARγ agonist ( P =  0·03). Serum IL-6 levels increased by 114 ± 31% (mean ± SE) in the entire group ( N  = 20) following the hyperinsulinaemic euglycaemic clamp ( P =  0·01) performed at study start. Twelve weeks of PPARγ agonist treatment significantly abrogated this insulin-stimulated increment in IL-6 levels compared to placebo ( P =  0·01). Furthermore PPARγ agonist treatment significantly lowered basal IL-4 levels ( P <  0·05).
Conclusions  (i) IL-6 levels increase during a hyperinsulinaemic clamp in GH replaced patients (ii) This increase in IL-6 is abrogated by PPARγ agonist treatment (iii) we hypothesize that PPARγ agonist-induced improvement of insulin sensitivity may obviate a compensatory rise in IL-6.     

The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index

Background  TSH secretion in hypopituitary patients may be decreased due to TSH deficiency but it also remains under feedback inhibition by free thyroxine (fT4). We propose a TSH index (TSHI), as 'fT4-adjusted TSH', that corrects for any physiological TSH suppression, to provide a true estimate of pituitary thyrotroph function and any pathological pituitary suppression.
Methods  A total of 9519 thyroid function tests (TFTs) (Bayer Immuno-1^®) 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 log TSH per change in fT4, which allowed the extrapolation of log TSH to a fixed fT4 of 0, defining the TSHI. TSHIs were compared with other measures of pituitary function.
Results  Feedback inhibition was estimated to cause a 0·1345 decrease in log TSH (mU/l) for 1 pmol/l increase in fT4 concentration, therefore TSHI = log TSH + 0·1345 × fT4. Patients with lower peak-stimulated GH and cortisol concentrations had a significantly lower TSHI ( P <  0·0001). TSHIs measured before pituitary stimulation tests predicted highly significantly the risk of test failure ( P =  0·0002). Of all potential fT4–TSH combinations within the current reference ranges, 21·9% were identified as abnormal on the basis of the TSHI.
Conclusion  The TSHI 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.     

Repeat endoscopic transsphenoidal surgery for acromegaly: remission and complications

Reported biochemical remission rates following surgical intervention for acromegaly range from 38 to 83 %. In patients not achieving surgical remission, few options remain, mostly limited to medical management and radiation therapy. There is debate over whether or not to offer reoperation to patients in whom surgical remission is not achieved with initial resection. Retrospective chart review was undertaken to determine all patients having acromegaly with persistently elevated GH and/or IGF-1 levels after initial pituitary adenoma resection, and who underwent reoperation using endoscopic endonasal approach at a single institution. Biochemical remission was defined as a postoperative GH level <1 ng/mL and a normal postoperative IGF-1 level in the absence of any medical therapy. In total, 14 patients underwent repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach. Of the 14 patients, 8 (57 %) achieved biochemical remission following repeat surgical intervention. Lower preoperative GH levels were associated with greater chance of biochemical remission (P = 0.048). New endocrinopathies were seen in 2 patients (14 %), and both were transient diabetes insipidus. Meningitis occurred in 2 patients (14 %); both were aseptic meningitis with no sequelae. No mortality was encountered. Repeat surgical intervention for acromegaly via endoscopic transsphenoidal approach appears safe and effective. With no mortality and minimal morbidity, repeat surgical intervention via endoscopic transsphenoidal approach appears a reasonable option for these hard-to-treat patients and should be considered for patients in whom surgical remission is not achieved with initial surgery.     

The Liege Acromegaly Survey (LAS): a new software tool for the study of acromegaly

Acromegaly is a chronic rare disease associated with negative pathological effects on multiple systems and organs. We designed a new informatics tool to study data from patients with acromegaly, the Liege Acromegaly Survey (LAS). This relational database permits the inclusion of anonymous historical and prospective data on patients and includes pathophysiology, clinical features, responses to therapy and long term outcomes of acromegaly. We deployed the LAS in a validation study at a single center in order to study the characteristics of patients with acromegaly diagnosed at our center from 1970-2011. A total of 290 patients with acromegaly were included (147 males and 143 females). There was a linear relationship between age at diagnosis and the date of diagnosis, indicating that older patients are being diagnosed with acromegaly more frequently. A majority presented with macroadenomas (77.5%) and the median diameter was 14 mm. Patients with macroadenomas were significantly younger than patients with microadenomas (P=0.01). GH values at diagnosis decreased with the age of the patients (P=0.01) and there was a correlation between GH values and tumor size at diagnosis (P=0.02). No correlation existed between insulin-like growth factor 1 (IGF-1) levels and tumor characteristics. The prevalence of diabetes was 21.4% in this population and 41.0% had hypertension. The presence of hypertension and diabetes were significantly associated with one another (P<0.001). There was a linear relation between initial GH and IGF-1 levels at diagnosis and those obtained during SSA analog treatment and the lowest GH and IGF-1 values following SSA therapy were obtained in older patients (GH: P<0.001; IGF-1: P<0.001). The LAS is a new relational database that is feasible to use in the clinical research setting and permits ready pooling of anonymous patient data from multiple study sites to undertake robust statistical analyses of clinical and therapeutic characteristics.