Bone mineral density in acromegaly: the effect of gender,disease activity and gonadal status

OBJECTIVE: Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status. DESIGN: Cross-sectional, retrospective. PATIENTS: We studied 152 acromegalic patients (99 women aged 26-72 years, and 53 men aged 21-75 years), 107 with active and 45 with controlled disease. Eighty-five patients had normal gonadal status and 67 were hypogonadal. MEASUREMENTS: In all patients we measured serum GH levels by immunoenzimometric assay, and serum IGF-I levels by radioimmunoassay. BMD was assessed at spine L2-L4 (LS) and at femoral neck (FN) by dual energy X-ray absorptiometry; results are expressed as Z-values. RESULTS: We evaluated the effect of GH excess on bone at different sites in relation to gonadal status, disease activity and gender. At LS, in respect to the reference population, BMD (mean +/- SE) values were higher in eugonadal patients (active: 0.71 +/- 0.29, P < 0.02; controlled: 0.65 +/- 0.28, P < 0.05) and lower in hypogonadal ones (active: -0.64 +/- 0.35, 0.1 < P < 0.05; controlled: -1.05 +/- 0.36, P < 0.01), regardless of disease activity. On the contrary, at FN, BMD was higher than in the reference population, both in eugonadal (1.01 +/- 0.22, P < 0.001) and hypogonadal (0.63 +/- 0.17, P < 0.001) patients only in subjects with active disease, but not in those in which the disease was controlled (eugonadal: 0.31 +/- 0.23, P = ns; hypogonadal 0.04 +/- 0.28, P = ns). We did not observe any difference in BMD values according to gender both at LS (males vs. females -0.02 +/- 0.30 vs. 0.01 +/- 0.24, P = ns) or at FN (0.77 +/- 0.19 vs. 0.63 +/- 0.15, P = ns). CONCLUSIONS: The anabolic effect of GH excess on bone in acromegalic patients is: (i) gender-independent; (ii) evident at the spine only in eugonadal regardless of disease activity; (iii) evident at femoral neck only in the presence of active disease regardless of gonadal status.     

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.     

Anaemia and marrow fibrosis in patients with primary hyperparathyroidism before and after curative parathyroidectomy

Objective  To determine the relationship between anaemia and myelofibrosis in patients with symptomatic primary hyperparathyroidism (PHPT) and to assess the effect of curative parathyroidectomy on anaemia and marrow fibrosis.
Design and methods  In this prospective follow-up study of 28 consecutive patients with symptomatic PHPT from January 2005 to June 2006, 15 patients were diagnosed with anaemia (haemoglobin < 130 g/l in males and < 120 g/l in females), eight (53%) of whom were finally recruited for the study. Complete blood cell count, serum calcium, phosphorus, alkaline phosphatase, intact PTH and 25-hydroxyvitamin D and bone marrow examination were performed both before and after parathyroidectomy in all ( n  = 8) patients, but bone marrow examination after surgery was performed only in those who had marrow fibrosis at baseline ( n  = 6).
Results  Anaemia was observed in 15 (53·3%) of the 28 patients with symptomatic PHPT. Normocytic normochromic anaemia that is characteristic of PHPT was found in 14 (50%) patients. Eight of the 15 patients with anaemia had a bone marrow examination and marrow fibrosis was observed in six (75%). Both anaemia and marrow fibrosis improved after successful parathyroidectomy, but improvement in anaemia was significant ( P =  0·02) only in those with marrow fibrosis at baseline. Marrow fibrosis did not correlate with duration of the disease ( P =  0·17), degree of hypercalcaemia ( P =  0·53) or serum levels of intact PTH ( P =  0·60).
Conclusions  Anaemia is common in patients with symptomatic PHPT, and was associated with marrow fibrosis in the majority of the patients who underwent bone biopsy. Both anaemia and marrow fibrosis improved after curative parathyroidectomy, but improvement in anaemia was noticeable only in those who had marrow fibrosis at presentation.     

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.     

Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome

Background  Prader–Willi syndrome (PWS) is a neurogenetic disorder characterized by muscular hypotonia, psychomotor delay, feeding difficulties and failure to thrive in infancy. GH treatment improves growth velocity and body composition. Research on the effects of GH on psychomotor development in infants with PWS is limited.
Objective  To evaluate psychomotor development in PWS infants and toddlers during GH treatment compared to randomized controls.
Design/patients  Forty-three PWS infants were evaluated at baseline. Twenty-nine of them were randomized into a GH group ( n  = 15) receiving 1 mg/m²/day GH or a non-GH-treated control group ( n  = 14). At baseline and after 12 months of follow-up, analysis with Bayley Scales of Infant Development II (BSID-II) was performed. Data were converted to percentage of expected development for age (%ed), and changes during follow-up were calculated.
Results  Infants in the GH group had a median age of 2·3 years [interquartile range (IQR) 1·7–3·0] and in the control group of 1·5 years (IQR 1·2–2·7) ( P =  0·17). Both mental and motor development improved significantly during the first year of study in the GH group vs. the control group: median (IQR) change was +9·3% (–5·3 to 13·3) vs. –2·9% (–8·1 to 4·9) ( P  < 0·05) in mental development and +11·2% (–4·9 to 22·5) vs. –18·5% (–27·9 to 1·8) ( P  < 0·05) in motor development, respectively.
Conclusion  One year of GH treatment significantly improved mental and motor development in PWS infants compared to randomized controls.     

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.     

Lower bone mineral density is associated with higher coronary calcification and coronary plaque burdens by multidetector row coronary computed tomography in pre- and postmenopausal women

Objectives  There is growing evidence for the association between bone mineral density (BMD) and vascular calcification, which is related to cardiovascular disease. Coronary multidetector row computed tomography (MDCT) is a noninvasive tool developed to evaluate coronary status precisely. We used MDCT to evaluate this association.
Design and patients  Eight hundred and fifteen subjects received routine checkups. After excluding subjects with factors affecting bone metabolism and cardiovascular disease, 467 subjects were analysed.
Measurements  Coronary calcification was measured with MDCT and BMD was measured with dual X-ray absorptiometry (DXA).
Results  The BMD of the femur and the lumbar spine (L-spine) were negatively associated with the coronary calcium score (CCS) after adjusting for age in women but not in men. This inverse correlation was stronger in women with a longer time since menopause ( r  = −0·35 at femur, postmenopausal women vs. r  = −0·10 at femur, premenopausal women, P  < 0·05), and it was stronger at the femur than in the L-spine ( r  =  − 0·35 at femur vs. r  =  − 0·16 at L-spine, P  < 0·01). The relationship was also stronger in postmenopausal women with osteoporosis and osteopaenia than in women with normal BMD. The lower BMD was associated with higher coronary plaque burdens and multidiseased coronary vessels in both men and women ( P <  0·01).
Conclusions  Increased CCS and subclinical atherosclerosis of plaque burdens as revealed by MDCT was associated with a low BMD in all women, independent of cardiovascular risk factors and age.     

Concentrations of the acute phase reactants high-sensitive C-reactive protein and YKL-40 and of interleukin-6 before and after treatment in patients with acromegaly and growth hormone deficiency

Background Acromegaly is accompanied by increased cardiovascular mortality and a cluster of proatherogenic risk factors. In the general population, ischaemic heart disease (IHD) is associated with elevated levels of inflammatory markers. The acute phase reactant (APR) C‐reactive protein (CRP) has been reported to be reduced in acromegaly and increase after treatment, suggesting that excess of GH/IGF‐I could have anti‐inflammatory effects. This is in accordance with results obtained in patients with growth hormone deficiency (GHD), where increased levels of CRP have been reported. Objective To investigate the hypothesis that the GH/IGF‐I system is a suppressive regulator of inflammatory processes. Subjects and methods Twenty‐one acromegalic patients and 19 GH‐deficient patients were studied. The two APRs CRP and YKL‐40 and the proinflammatory cytokine interleukin‐6 (IL‐6) were measured before and after treatment and in healthy matched controls. Results In acromegalic patients, serum concentrations of high‐sensitive CRP (hsCRP) and YKL‐40 were reduced compared to controls (P < 0·001) and increased (P < 0·001) after treatment, together with IL‐6 (P = 0·021), to levels comparable with controls. Pretreatment serum YKL‐40 and IL‐6 showed a significant inverse correlation with IGF‐I and GH. In GH‐deficient patients, hsCRP and YKL‐40 were elevated compared to controls (P = 0·001 and P = 0·048). During treatment, levels of both APRs showed a trend towards a decrease (P = 0·087 and P = 0·060), and after treatment, levels of YKL‐40 no longer differed from that of controls. Serum IL‐6 was not different from controls and did not change during GH treatment. Conclusion The results point to the possibility of a relationship between GH disturbances and inflammatory processes.     

Factors associated with bone metabolism in acromegalic patients: hypogonadism and female gender.

The purpose of the study was to determine the factors associated with bone metabolism in acromegalic patients. Thirty three patients with acromegaly who had been followed on a regular basis in the endocrinology clinic were enrolled for the study. Among the factors acting upon bone metabolism, age, gender, body mass index (BMI), duration and activity of the disease, length of remission, treatment modalities and functional status of the pituitary were evaluated. Their influences on the determinants of bone remodelling and bone mineral density (BMD) were tried to be elucidated. The median age of the 33 acromegalics (19 females, 14 males) was 39.73 +/- 10.1 years. Twenty-three patients (9 males and 14 females) were eugonadal. Ten patients had been diagnosed with history of at least one year of untreated hypogonadism (5 males and 5 females; for 1 - 10 years). The BMD values of the lumbar vertebrae, the femur and the radius were correlated with each other. Patients were grouped according to their T-scores as decreased, normal, and increased BMD. Groups were similar with regard to age, BMI, gender, duration of disease, and remission, GH, IGF-1, IGFBP-3 levels, markers of bone turnover. Presence of hypogonadism and duration of hypogonadism revealed statistically significant difference among the 3 groups (p = 0.005 and p = 0.035, respectively). Hypogonadal acromegalic patients had decreased BMD compared to eugonadal acromegalics and healthy population while the eugonadal female acromegalic patients revealed increased BMD of lumbar vertebrae, femur, and distal radius compared to the sex-matched healthy population.     

Octreotide LAR vs. surgery in newly diagnosed patients with acromegaly: a randomized, open-label, multicentre study

Objective  This prospective randomized study evaluated the efficacy and safety of octreotide LAR vs. surgery in newly diagnosed acromegalic patients.
Methods  Totally 104 male and female patients were enrolled in a 50-week, exploratory, open-label and randomized study. Eligible patients were randomized to receive either octreotide LAR 20 mg every 28 days or to undergo surgery. Efficacy was assessed by changes in mean GH and IGF-I serum concentrations, at weeks 12, 24 and 48. Tumour volume was assessed by contrast-enhanced MRI. In both groups, treatment adjustment was performed for patients uncontrolled at week 12 or 24. Octreotide LAR patients received a dose increased to 30 mg or, if already receiving this dose, investigator and patients could decide to cross-over to surgery. Patients uncontrolled after surgery received octreotide LAR 20 mg, increased to 30 mg if acromegaly was still uncontrolled.
Results  Overall success rates at weeks 24 and 48 were 25% and 28% for the octreotide LAR group and 49% and 39% for the surgery group. Only the difference observed at week 24 was statistically significant ( P =  0·047). Both groups had a significant (> 20%) tumour shrinkage: 73% of patients in the octreotide LAR group and 95% in the surgery group. Major differences between octreotide LAR and surgery group in the occurrence of adverse events were gastrointestinal (71% vs. 27%), hepatobiliary (41% vs. 8%) and respiratory (5% vs. 28%).
Conclusion  This first randomized study in unselected patients indicates that the 48-week treatment outcome of octreotide LAR as first-line treatment of acromegaly does not significantly differ from surgery. As a complete response to surgery in GH-secreting macro-adenomas can be difficult, first-line therapy with octreotide LAR can be considered as a viable alternative for most patients with acromegaly, due to its low complication rate.     

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.     

Does partial surgical tumour removal influence the response to octreotide‐LAR in acromegalic patients previously resistant to the somatostatin analogue?

Objective To compare the intrapatient response to the same dose of slow‐release octreotide (OCT‐LAR) before and after noncurative surgery in acromegalic patients who did not attain disease control after primary treatment with OCT‐LAR. Design Prospective clinical study. Patients Eleven acromegalic patients (eight men, aged 42·45 ± 11·15 years, 10 macroadenomas) received OCT‐LAR (20 mg, n = 1; 30 mg, n = 10) every 28 days as the primary treatment (1stOCT‐LAR) for 11·3 ± 4·2 months, without IGF‐I normalization. They were subsequently submitted to surgery without cure and were then treated with the same dose of OCT‐LAR for 8·0 ± 6·5 months (2ndOCT‐LAR). Measurements GH and IGF‐I serum concentrations were obtained under basal conditions as well as during treatment. Pituitary tumour volume was assessed by magnetic resonance imaging (MRI) of the sella. IGF‐I was also expressed as a percentage of the upper limit of the normal age‐ and sex‐matched range (%ULNR IGF‐I). Results After 1stOCT‐LAR, there was a decrease in GH levels (P = 0·003) and %ULNR IGF‐I (P = 0·009) compared to baseline (B), but no IGF‐I normalization. Tumour shrinkage was observed in eight of 10 patients with macroadenomas (median 63·7%, range 24·5–75·5%). After surgery, mean levels of GH and %ULNR IGF‐I were lower than those at baseline (P = 0·0004 and P = 0·003, respectively), but not when compared to values during 1stOCT‐LAR (P = 1·000 and P = 0·957, respectively). MRI confirmed surgical tumour removal (median 64%, range 4·9–96·6%) in eight of the 10 patients. Comparing the 2ndOCT‐LAR results with postsurgical results, there were no significant decrease in %ULNR IGF‐I (P = 0·061) and GH levels (P = 0·414). Nine patients (82%) achieved IGF‐I normalization. The degree of surgical tumour reduction did not correlate with IGF‐I normalization (P = 0·794). When comparing the results between 1stOCT‐LAR and 2ndOCT‐LAR, there was a decrease, albeit not statistically significant, in serum GH levels (P = 0·059) and a significant decrease in %ULNR IGF‐I (P = 0·011). Conclusions Using strict criteria (same patient, same drug, same dose) our results strongly suggest that the surgical reduction of tumour mass can improve the outcome of OCT‐LAR treatment in acromegalic patients resistant to primary therapy with SA.     

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.     

Age and sex as predictors of biochemical activity in acromegaly: analysis of 1485 patients from the German Acromegaly Register

Objective  We evaluated the German Acromegaly Register for clinical variables associated with the initial biochemical activity of patients with acromegaly.
Design  Retrospective analysis of data in the registry.
Patients   A total of 1485 patients with acromegaly (males 45·6%, females 54·4%) were treated in 42 German endocrine centres until November 2005. Linear regression models were used to estimate the influence of various parameters on biochemical activity.
Results  Male patients with acromegaly were significantly younger at the time of diagnosis than female patients (41 vs. 47 years, P  < 0·0001) and had significantly higher random GH levels than females (21 vs. 14 ng/ml, P  < 0·005) and IGF-1 levels (773 vs. 679 ng/ml, P  < 0·0001), respectively. Age at initial presentation turned out to be the most important independent risk factor associated with random GH levels, oral glucose tolerance test-suppressed GH levels, IGF-1 levels, body mass index (BMI), tumour size and prevalence of hypopituitarism. Sex was an independent risk factor for IGF-1 levels, BMI and prevalence of hypopituitarism. Tumour size was an independent risk factor for both GH and IGF-1 levels.
Conclusions  In summary, initial biochemical activity of acromegaly is influenced by patient's age and to a lesser degree by patient's sex. Male patients are on an average 6 years younger than females.     

Perioperative plasma active and total ghrelin levels are reduced in acromegaly when compared with in nonfunctioning pituitary tumours even after normalization of serum GH

Objective Ghrelin is a novel gastric peptide known to stimulate GH secretion, but the relationship between ghrelin and the GH‐insulin‐like growth factor (IGF)‐1 axis in GH excess or deficiency is poorly understood. This study investigated dysregulation of ghrelin secretion in acromegaly and its short‐term postoperative recovery. Methods A prospective study was conducted on eight patients who underwent complete transsphenoidal resection of GH‐producing pituitary adenomas (acromegaly group) and 22 for endocrinologically nonfunctioning pituitary tumours (control group). Active and total plasma ghrelin levels were measured serially before and after surgery. Results Preoperative active and total plasma ghrelin concentrations (mean ± SD; fmol/ml) were significantly reduced in acromegalic patients when compared with those in the controls (9·6 ± 4·3 and 157·4 ± 65·6 vs. 21·8 ± 13·0 and 267·1 ± 111·4; P = 0·023 and P = 0·021, respectively). Both levels were still significantly suppressed on postoperative Day 7 in the acromegaly group when compared with those in the control group (11·7 ± 4·3 and 197·8 ± 68·9 vs. 22·5 ± 12·6 and 302·7 ± 100·0; P = 0·038 and P = 0·018, respectively). The ratios of active to total ghrelin were not significantly different between the two groups before and after operation. In acromegalic patients, active and total ghrelin levels remained significantly suppressed even after normalization of serum GH levels. Conclusions The putative negative feedback mechanism of GH on ghrelin secretion may in part account for the low ghrelin levels observed in acromegalic patients, and the mechanism may persist even after normalization of serum GH.     

Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension

Background  It has previously been shown that higher serum TSH is associated with increased thyroid cancer incidence and advanced-stage disease. In the healthy adult population, mean TSH increases with age. As age over 45 years is a known prognostic indicator for thyroid cancer, it is important to know whether higher TSH in patients with thyroid cancer occurs independent of age.
Objective  To determine the relationship between higher TSH, cancer and age.
Design  A retrospective cohort study.
Patients and methods  A total of 1361 patients underwent thyroid surgery between May 1994 and December 2007 at a single institution. Of these patients, 954 had pathological data, preoperative TSH and complete surgical history available. Data were analysed in relation to age and TSH.
Results  Mean TSH was significantly higher in cancer patients regardless of age < 45 years or ≥ 45 years ( P =  0·046 and P  = 0·027, respectively). When examining age groups < 20, 20–44, 45–59 and ≥ 60 years, there was a trend of rising mean TSH with age. Despite the rise in the benign subgroups, mean TSH was consistently higher in those with cancer vs. those without. On multivariate analysis, higher TSH was independently associated with cancer ( P =  0·039) and pathological features of Hashimoto's thyroiditis ( P =  0·001) but not with age ( P =  0·557). On multivariate analysis of high-risk features associated with poor prognosis, there was a significant association between higher TSH and extrathyroidal extension ( P =  0·002), whereas there was no clear relationship with age, tumour size > 4 cm, and distant metastases.
Conclusion  Independent of age, thyroid cancer incidence correlates with higher TSH. Higher TSH is associated with extrathyroidal extension of disease.     

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.     

Reduced levels of GH during GnRH analogue treatment in pubertal short girls born small for gestational age (SGA)

Context  Several studies showed a decrease in height velocity during GnRH analogue (GnRHa) treatment. No information is available on GH levels during GnRHa treatment in short SGA girls.
Objective  To study overnight GH profiles and IGF-I and IGFBP-3 levels in girls with Tanner stage 2 and stage 3, before and after 3 months of GnRHa treatment, and to compare levels with those found in prepubertal short SGA girls.
Patients  Twenty-four pubertal and 16 prepubertal short SGA girls.
Intervention  After baseline overnight GH profiles, pubertal girls received leuprorelide acetate depots of 3·75 mg subcutaneously every 4 weeks.
Outcome measures  GH, IGF-I and IGFBP-3 levels.
Results  At baseline, GH levels were comparable to levels found in prepubertal short SGA girls and IGF-I and IGFBP-3 SDS were significantly below the population mean. After 3 months of GnRHa treatment, AUC₀ ( P  = 0·02), mean ( P  = 0·02) and maximum GH levels ( P  = 0·008) had significantly decreased. Mean GH levels were significantly lower than in prepubertal short SGA girls ( P  = 0·03). Eight girls with more than 40% decrease in mean GH levels also had a significantly greater decrease in IGF-I and IGFBP-3 levels. Mean and maximum GH levels at baseline correlated significantly with those after 3 months of GnRHa treatment.
Conclusion  Short SGA girls lack the normal increase in GH levels seen in puberty and have reduced IGF-I and IGFBP-3 levels, which might explain their reduced pubertal growth spurt. GnRHa treatment led to a significant reduction in GH levels. Therefore, combining GnRHa treatment with GH treatment might improve adult height of short SGA girls.     

Does the RET variant G691S influence the features of sporadic medullary thyroid carcinoma?

Objective  The RET (rearranged during transfection) proto-oncogene G691S variant is over-represented in the germline of patients with sporadic medullary thyroid carcinoma (sMTC) vs. normal controls but so far is not associated with any medical or pathological features of the tumour. The aim of our study was to assess the influence of this variant on the age of onset, clinical, biological and pathological features of sMTC.
Design and patients  One hundred patients with histologically proven MTC, for whom the germline genetic analysis of RET was negative and medical records were available, were included in the study.
Results  Patients with the heterozygous GS variant or the homozygous SS variant ( n  = 36) were on average 8·0 years younger than patients with the wild-type GG variant ( n  = 64, mean age 43·9 vs. 51·9 years, P  < 0·01). The former group did not differ from the wild-type group in terms of MTC size, prevalence of C-cell hyperplasia (CCH) or papillary thyroid carcinoma (PTC). However, the prevalence of an increased preoperative basal calcitonin (bCT) level (> 1000 pg/ml) was 2·75-fold higher in the patients with the GS or SS variant than in those with the wild-type variant ( P <  0·001). The proportion of patients with lymph node metastases was also higher in the former group ( P <  0·05). Multivariate analysis confirmed that the presence of the RET variant is independently associated with higher preoperative bCT values ( P =  0·011).
Conclusions  Our data demonstrate that the RET G691S variant could modulate the age of onset of sMTC as demonstrated previously for familial tumours. Moreover, this variant is an independent predictor of a higher basal calcitonin synthesis rate in patients with sMTC.