Circulating levels of pegvisomant and endogenous growth hormone during prolonged pegvisomant therapy in patients with acromegaly.

OBJECTIVE: To investigate whether pegvisomant treatment in acromegaly induces gradual elevations in endogenous serum growth hormone (GH) levels and whether serum pegvisomant levels predict the therapeutic outcome. PATIENTS AND METHODS: Seventeen patients (6 women), mean age 46·3 years (range: 23·2-76·2), were studied. For each patient, four hospital visits were identified including 'active disease' (no treatment) and last follow-up. At each visit, 12 blood samples were drawn during 3 h including an oral glucose tolerance test (OGTT). Eight patients received a somatostatin analogue in addition to pegvisomant on the last visit. RESULTS: Median (range) pegvisomant doses (mg/day) were 10 (10-10), 15 (10-15) and 15 (10-15) at visits 2, 3 and 4, respectively, and the mean duration of pegvisomant treatment was 17·5 ± 3·2 (SEM) months. Serum IGF-I changed significantly during the treatment period with the highest level at baseline and lowest levels at visits 3 and 4. GH levels increased in a dose-dependent manner during pegvisomant treatment and decreased at visit 4. Changes in IGF-I levels correlated negatively with changes in serum pegvisomant levels between visits. Serum pegvisomant at each visit correlated with baseline growth hormone levels, whereas no associations between serum pegvisomant and either dose, gender, age or body weight were found. CONCLUSIONS: (1) Serum GH levels increased initially, but remained stable during prolonged pegvisomant treatment in patients with acromegaly, (2) serum pegvisomant levels predicted the reduction in serum IGF-I during treatment and (3) the interindividual variation in serum pegvisomant levels seems not predicted by either age, gender or body composition.

Determination of free growth hormone.

CONTEXT: Approximately 50% of circulating GH is bound to the high-affinity GH-binding protein (GHBP), which is known to affect the pharmacokinetics, bioactivity, and quantitative determination of GH. Nevertheless, the presence of GHBP is rarely taken into account in the clinical use of GH measurements. OBJECTIVE: Our objective was to develop an assay for free GH in serum. METHODS: We used ultrafiltration by centrifugation. Due to the small molecular difference between GH and GHBP, the size of GHBP and GHBP-GH complexes was increased by preincubation of serum with a monoclonal GHBP antibody (MAb 263). RESULTS: The ultrafiltration membrane almost completely retained all GHBP (>98.5%) and allowed free passage of unbound GH (>98.4%). Addition of increasing concentrations of GHBP reduced free GH dose dependently, and measured and calculated levels of free GH changed in parallel. During an insulin-tolerance test, free and total GH changed in parallel in all individuals (n = 11) and their peak values as well as area under the curve values were positively correlated (r = 0.89; P < 0.001 and r = 0.92; P < 0.001, respectively). Of note, the relative levels of free GH (calculated as the area under the curve of free to total GH) was inversely correlated with GHBP (r = -0.94; P < 0.001). CONCLUSION: It is possible to measure free GH in human serum. Free GH correlated positively with total GH and inversely with GHBP. Measurement of free GH may be a helpful future tool in the management of GH disorders and in studies of GH-GHBP interrelationships.

Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese.

Zinc ions influence adipose tissue metabolism by regulating leptin secretion and by promoting free fatty acid release and glucose uptake. The mechanisms controlling zinc metabolism in adipose tissue are unknown. We therefore examined the gene-expression levels of a number of zinc-transporting proteins in adipose tissue, comparing subcutaneous fat with visceral fat from lean and obese humans. Both ZnT-proteins responsible for zinc transport from cytosol to extracellular compartments and intracellular vesicles and Zip-proteins responsible for zinc transport to the cytoplasm were expressed in all samples. This suggests that zinc metabolism in adipocytes is actively controlled by zinc-transporters. The expression levels were different in lean and obese subjects suggesting a role for these proteins in obesity. Furthermore, the expression levels were different from subcutaneous fat to intra-abdominal fat suggesting that the metabolic activity in adipocytes is to some extent dependent upon zinc and the activity of zinc-transporting proteins or vice versa.

Assessment of hydration by means of bioelectrical impedance and arm muscle area during growth hormone (GH) replacement therapy: A prospective study of 130 GH-deficient patients.

OBJECTIVE: Growth hormone (GH)-deficiency is associated with a reduced extracellular volume (ECV), whereas GH replacement may cause fluid retention. We have tested a simple method to assess hydration in GH-deficient patients (GHD) based on concomitant measurements of body resistance by bioelectrical impedance analysis (BIA), and arm muscle area (AMA). DESIGN: We prospectively followed 130 patients (54 females, 76 males) with adult-onset GHD before and during 1-5 years GH replacement therapy. METHODS: Concomitant measurements of body resistance and AMA were done on four occasions: before treatment, after one month and one year of treatment, and at the most recent visit. Based on normative data obtained in 142 women and 84 men an inverse relationship was documented between body resistance and AMA. Assuming that linear height and the concentration of electrolytes remain constant, body resistance at a given AMA will reflect specific hydration. RESULTS: In the patients a gender-specific inverse correlation between body resistance and AMA existed, which was different from the control group and changed during GH replacement. A deviation between predicted (based on normative data) and measured body resistance at a given AMA was recorded in the patients before and during therapy compatible with relative dehydration in the untreated state followed by an increase in hydration during therapy. CONCLUSIONS: Concomitant measurements of BIA and AMA in GHD patients may provide a non-invasive and simple means to estimate hydration before and during GH replacement.

Growth hormone (GH) substitution in GH-deficient patients inhibits 11beta-hydroxysteroid dehydrogenase type 1 messenger ribonucleic acid expression in adipose tissue.

CONTEXT: Local tissue activity of glucocorticoids is in part determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) and 11beta-HSD2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a central role in the features of GH deficiency and the metabolic syndrome. OBJECTIVE: We investigated the effects of GH treatment on adipose tissue 11beta-HSD mRNA. SUBJECTS AND METHODS: A randomized placebo-controlled double-blind study design was used. Twenty-three GH-deficient patients (16 males and seven females) were randomized to 4 months of GH treatment (2 IU/m2) (n = 11) or placebo treatment (n = 12). Adipose tissue biopsies and blood samples were obtained before and after treatment. Biopsies were obtained from the abdominal sc depot at the level of the umbilicus and do not necessarily reflect the metabolically more important visceral adipose tissue. Gene expressions were determined by real-time RT-PCR. RESULTS: GH treatment decreased 11beta-HSD1 mRNA 66% [95% confidence interval (CI), 23-107%; P < 0.01] and increased 11beta-HSD2 mRNA 167% (95% CI, 33-297%; P < 0.05) in adipose tissue. Serum IGF-I and IGF-I mRNA increased in the GH-treated group by 187% (95% CI, 122-250%; P < 0.001) and 470% (95% CI, 88-846%; P < 0.01). The change in 11beta-HSD1 mRNA expression was negatively correlated with the change in serum IGF-I (R = -0.434; P < 0.05). In contrast, the change in 11beta-HSD2 mRNA expression was positively correlated with the change in serum IGF-I (R = 0.487; P < 0.05), and even stronger with the change in IGF-I mRNA expression (R = 0.798; P < 0.0001). CONCLUSION: GH treatment is able to decrease 11beta-HSD1 mRNA and increase 11beta-HSD2 and accordingly may be able to reduce the amount of locally produced cortisol in adipose tissue.

Kinetics and secretion of placental growth hormone around parturition.

OBJECTIVE: During pregnancy, placental growth hormone (PGH) is secreted into the maternal circulation, replacing pituitary GH. It is controversial whether PGH levels decline during vaginal birth. After placental expulsion, PGH is eliminated from the maternal blood. GH binding protein (GHBP) and body mass index (BMI) influence GH kinetics, but their impact on PGH kinetics is unknown. The present study was undertaken to define the kinetics of PGH during vaginal delivery and Caesarian section and to relate these kinetics to GHBP and BMI. DESIGN: A short term, prospective cohort study. METHODS: Twelve women had repeated blood samples drawn during vaginal delivery. From 26 women undergoing planned Caesarian delivery (CS) repeated blood samples were withdrawn before, during and after the CS, allowing PGH half-life determination. RESULTS: During vaginal delivery, median PGH values did not change before expulsion of the placenta, although individual fluctuations were seen. Clearance of PGH from the maternal circulation was best described by a two-compartment model. The initial half-life of serum PGH was (mean +/- s.d.) 5.8 +/- 2.4 min, and the late half-life was (median) 87.0 min (range: 25.1-679.6 min). The late half-life was correlated to the pre-gestational BMI (r = 0.39, P = 0.047), but not to the serum GHBP concentration. CONCLUSIONS: Serum PGH did not decrease significantly during vaginal delivery. Elimination of PGH fitted a two-compartment model, with an estimated initial half-life of 5.8 min. The late phase serum half-life of PGH was related to BMI, suggesting a role for maternal fat mass in PGH metabolism.

Physiology and pathophysiology of growth hormone-binding protein: methodological and clinical aspects.

Circulating GH is partly bound to a high-affinity binding protein (GHBP), which in humans is derived from cleavage of the extracellular domain of the GH receptor. The precise biological function GHBP is unknown, although a regulation of GH bioactivity appears plausible. GHBP levels are determined by GH secretory status, body composition, age, and sex hormones, but the cause-effect relationships remain unclarified. In addition to the possible in vivo significance of GHBP, the interaction between GH and GHBP has methodological implications for both GH and GHBP assays. The present review concentrates on methodological aspects of GHBP measurements, GHBP levels in certain clinical conditions with a special emphasis on disturbances in the GH-IGF axis, and discusses the possible relationship between plasma GHBP and GH receptor status in peripheral tissues.

Pain perception after subcutaneous injections of media containing different buffers.

Several hormones are administered by daily subcutaneous injections. Pain caused by subcutaneous injection is an unpleasant condition, which can limit patient compliance. The objective of the present study was to evaluate the perception of pain by subcutaneous injection of two different and commercially available solutions for dispensing recombinant human growth hormone. The solutions are characterised by pH, conservation, and buffer. Isotonic saline was used as reference solution. Fifty-four healthy volunteers (mean age (+/-S.E.M.): 35.5+/-1.1 years) were recruited to the double-blind, randomised study. All injections were performed pairwise (right and left thigh) in one day by the same experienced nurse. Perception of pain was evaluated by the volunteers immediately after injection and 2 min. after injection into the thigh of three formulations, which differed with respect to pH and buffers (histidine, citrate and saline, respectively). Significantly more participants (38/54) found than the citrate buffer caused more pain than the histidine buffer immediately after injection (P=0.002). Histidine buffer did not cause more pain than saline (P=0.996). After 2 min., there was no difference between the histidine and the citrate buffer (P=1.00), nor between the histidine buffer and saline (P=1.00). In summary, the solution-containing citrate as buffer caused more pain after subcutaneous injection than the solution with histidine as buffer. Considering patient compliance, it seems advisable to employ histidine-buffered solution rather than citrate-buffered solution for dispensing recombinant human growth hormone by daily subcutaneous injections.

Discontinuation of estrogen replacement therapy in GH-treated hypopituitary women alters androgen status and IGF-I.

OBJECTIVE AND DESIGN: Compared with their male counterparts, healthy females secrete more growth hormone (GH) and those with GH-deficiency have lower insulin-like growth factor I (IGF-I) levels and are less responsive to GH substitution. To test whether this gender difference is related to sex hormones we measured androgen status and IGF-I related parameters in 38 hypopituitary women (mean (range) age 41.5 (20-58) years) during continued GH substitution as compared with a control group of 38 healthy women matched for age and menopausal status. Twenty six patients were studied twice: with estrogen replacement and after 28 days of estrogen discontinuation in a randomised design. RESULTS: The patients were androgen deficient compared with controls (median, range), dehydroepiandrosterone sulphate (DHEAS): 185 (99-7800) nmol/l vs 4400 (820-13,000) nmol/l, P=or<0.001; androstenedione: 0.5 (0.1-7.1) nmol/l vs 4.3 (1.6-8.8) nmol/l, P=or<0.001; dihydrotestosterone (DHT): 0.13 (0.09-0.54) nmol/l vs 0.55 (0.09-0.89) nmol/l, P=or<0.001; testosterone: 0.28 (0.09-1.56) nmol/l vs 1.1 (0.71-2.24) nmol/l, (P=or<0.001); free testosterone: 0.004 (0.001-0.030) nmol/l vs 0.016 (0.001-0.030) nmol/l, P=or<0.001. The circulating levels of IGF-I, IGF-II, IGF-binding protein 1 (IGFBP-1), and IGFBP-3 did not differ between patients and controls. The subgroup of patients receiving hydrocortisone (HC) replacement (n=24) had significantly lower levels of androgens (suppressed by 80-100%) as well as IGF-I and IGFBP-3 as compared with the patients not receiving HC. IGF-I was correlated to free testosterone in patients (r=0.57, P=0.0005) as well as controls (r=0.43, P=0.008), and free testosterone was a significant positive predictor of IGF-I. Estrogen discontinuation induced an increase in IGF-I (167+/-15 vs 206+/-14 microg/l, P=0.005 and IGFBP-3 (3887+/-139 vs 4309+/-138 microg/l, P=0.0005). Estrogen discontinuation was associated with a significant increase in median (range) free testosterone (0.004 (0-0.02) vs 0.0065 (0-0.03) nmol/l, P=0.001) and a significant decrease in median (range) sex-hormone binding globulin (SHBG; 93 (11-278) vs 55.5 (20-142) nmol/l, P=0.001). DeltaIGF-I correlated with DeltaSHBG (r=-0.45 P=0.033) and DeltaIGFBP-3 (r=0.67 P=or<0.001). In a regression model DeltaE2, Deltatestosterone, DeltaSHBG and DeltaIGFBP-3 explained 93% of the variation in DeltaIGF-I. CONCLUSIONS: Androgen levels are low in hypopituitary women and free testosterone correlates with IGF-I. Discontinuation of estrogen replacement in these patients induces elevations in IGF-I as well as free testosterone, and DeltaIGF-I correlated positively with Deltafree testosterone. These effects may contribute to the gender differences observed in the GH-IGF axis in healthy adults as well as in the responsiveness of hypopituitary patients to GH substitution.

Very short term dehydroepiandrosterone treatment in female adrenal failure: impact on carbohydrate, lipid and protein metabolism.

OBJECTIVE: In female adrenal insufficiency, dehydroepiandrosterone (DHEA) secretion is impaired and circulating androgen levels are severely reduced. We wanted to analyse the acute effects of physiological DHEA substitution on substrate metabolism. DESIGN: We studied nine females with adrenal insufficiency after 9 days of oral DHEA replacement (50 mg/day) in a double-blind, placebo-controlled crossover study. METHODS: Whole body and regional substrate metabolism was assayed in the basal state and during a euglycemic hyperinsulinemic glucose clamp by means of isotope dilution techniques (glucose, phenylalanine, tyrosine), indirect calorimetry and in situ lipolysis (microdialysis technique). RESULTS: DHEA treatment normalized the levels of all androgens. Basal and insulin-stimulated total energy expenditure and rates of protein, lipid and glucose oxidation were unaffected by DHEA. Whole body turnover of glucose and protein were also unaffected by DHEA. Forearm breakdown of protein was reduced by insulin to the same extent after placebo and DHEA. Insulin sensitivity as expressed by the glucose infusion rate during the euglycemic clamp was similar after placebo and DHEA. Finally, the interstitial release of glycerol in adipose tissue was not significantly influenced by DHEA. CONCLUSIONS: Short-term oral DHEA replacement in women with adrenal insufficiency was not associated with measurable changes in total or regional substrate metabolism.

Growth hormone binding protein and maternal body mass index in relation to placental growth hormone and insulin requirements during pregnancy in type 1 diabetic women.

In pregnancy, the growth hormone axis is shifted from pituitary growth hormone (GH) to placental growth hormone (PGH). Their common binding protein, GH binding protein (GHBP), displays peak serum levels at mid-gestation in normal individuals. In the non-pregnant state, diabetes is known to be associated with elevated levels of GH and decreased levels of insulin-like growth factors (IGFs) and GHBP. Diabetes in pregnancy may therefore as well be associated with disturbances in the growth hormone axis. In the present study, we aimed at investigating the impact of GHBP and maternal body mass index (BMI) on levels of PGH, thereby enabling estimation of any association between free PGH and weight adjusted insulin requirements. In 51 type 1 diabetic women, blood samples were collected in gestational week 10+, 16+, 22+, 28+ and 34+, and analysed for their serum content of GHBP, PGH, and GH. Serum GHBP increased from the first weeks of pregnancy to median 2.07 nmol/l (range 1.17-4.26) in week 22+, then declined to median 1.29 nmol/l (range 0.77-2.35) in week 34+ (ANOVA P < 0.001). Serum PGH levels were highest in week 34+ at median 21.3 microg/l (range 5.1-165.4) (P < 0.001), whereas a steady decrease in GH values was observed throughout pregnancy to a median 0.17 microg/l (range 0-5.53). The fraction of calculated free PGH to total PGH increased from mid-gestation onwards to 55.2% (37.0-87.1) in week 34+ at a median level of free PGH of 10.4 microg/l (range 1.9-144.0) (P < 0.001). Similarly, the molar ratio of total PGH to GHBP increased to a maximum of 0.68 (0.12-6.62) in week 34+. As in normal pregnancies, the correlation between BMI and GHBP was lost in late pregnancy. The newborns birth weight z-score correlated with total PGH and derivatives here-of in week 34+. Neither total nor weight adjusted insulin requirements correlated to total PGH, calculated free PGH, nor GHBP. In conclusion, PGH and GHBP display a similar course during pregnancy in type 1 diabetic women as described in normal women. The well-known association between GHBP and BMI was lost in late pregnancy. Calculated levels of free PGH were positively associated to fetal growth, but not to maternal insulin requirements.

Growth hormone increases vascular cell adhesion molecule 1 expression: in vivo and in vitro evidence.

We investigated the impact of GH administration on endothelial adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, in vivo and in vitro. Soluble VCAM-1, E-selectin, and C-reactive protein concentrations were measured before and after treatment in 25 healthy subjects and 25 adult GH-deficient (GHD) patients randomized to GH treatment or placebo. Furthermore, we studied the direct effect of GH and IGF-I and serum from GH-treated subjects on basal and TNF alpha-stimulated expression of VCAM-1 and E-selectin on cultured human umbilical vein endothelial cells. Baseline levels of VCAM-1, but not E-selectin, were significantly lower in GHD patients than in healthy subjects (362 +/- 15 microg/liter vs. 516 +/- 21 microg/liter, P < 0.001) and increased in GHD patients during GH treatment, compared with placebo [net difference between groups 151.8 microg/liter (95% confidence interval: 95.0-208.7 microg/liter); P < 0.0001]. In human umbilical vein endothelial cells, there was no direct stimulatory effect of either GH or IGF-I on the expression of VCAM-1 and E-selectin, but serum from GH-treated healthy subjects significantly increased the expression of VCAM-1 (P < 0.01). Our findings are compatible with the notion that GH may stimulate the expression of VCAM-1 indirectly through modulation of circulating factors. VCAM-1-mediated leukocyte extravasation is implicated in several illnesses including atherosclerosis and multiple-organ failure in sepsis, and we hypothesize that enhanced expression of VCAM-1 may contribute to the detrimental effects of GH in critically ill patients.

Gene expression of the GH receptor in subcutaneous and intraabdominal fat in healthy females: relationship to GH-binding protein.

OBJECTIVE: Circulating GH-binding protein (GHBP) is produced by proteolytical cleavage of the extracellular part of the GH receptor (GHR) and is positively correlated to the amount of body fat. To test the hypothesis that adipose tissue may contribute to the production of circulating GHBP, we compared gene expression of two GHR isoforms in adipose tissue with serum GHBP concentrations in healthy females. DESIGN: Twenty-two healthy females undergoing surgery for benign gynecological conditions were included in the study. METHODS: During surgery, s.c. and intraabdominal fat biopsy samples were taken. Gene expression of the full-length GHR and a truncated GHR (GHRtr) was assessed by RT-PCR relative to the expression of beta-actin. RESULTS: The full-length GHR was expressed to a much higher level than GHRtr in both tissues. The levels of both GHR and GHRtr mRNA were similar in intraabdominal and s.c. adipose tissues. Surprisingly, concentrations of circulating GHBP were negatively correlated to the levels of mRNA transcripts of both the full-length GHR and GHRtr in intraabdominal fat. Whole body resistance (as a measure of lean body mass) was positively correlated to mRNA levels for both GHRs in intraabdominal fat. CONCLUSIONS: (i) The full-length GHR is expressed to a much higher level than GHRtr in s.c. as well as visceral abdominal fat; (ii) the observation of a significant correlation between GHR expression and GHBP levels further emphasizes the link between adipose tissue and GHBP; (iii) it remains, however, to be demonstrated whether circulating GHBP is produced to a significant degree by adipose tissue.

Biochemical definitions of disease activity in acromegaly.

UNLABELLED: In acromegaly the therapeutic outcome is difficult to assess and depends on the biochemical method. We have ascertained disease activity in 70 acromegalic patients by means of a GH profile (8 hourly samples) and a single IGF-I measurement as compared to a healthy control group. As an estimate of the "stiffness" of the GH profile we calculated the SD/nadir(GH) from the GH profile. In the control group the following upper normal limits were obtained: IGF-I (microg/l) 217; mean GH (microg/l) 2.16; nadir GH (g/l) 0.3. Based on ROC plot analysis a value of 2.0 for the SD/nadir ratio was used as cut-off. This translated into the following surgical cure rates (%): IGF-I 47; mean GH 77; nadir GH 65; SD/nadir 30. Some of the patients post-surgery had elevated IGF-I levels despite "normal" GH levels. Abnormal SD/nadir versus normal IGF-I and vice versa were recorded in many patients post-surgery. IN CONCLUSION: (1) cure rates of acromegaly depend strongly on the criteria being used and (2) estimates of GH secretion pattern may yield important information about GH status in acromegaly.

Evaluation of growth hormone stimulation tests in cured acromegalic patients.

UNLABELLED: We have evaluated the GH peak response to insulin tolerance test (ITT) and to GHRH+arginine in 11 patients cured of acromegaly after treatment with surgery/radiotherapy and compared them to a control group matched for age and sex. GH peak response was significantly higher in the control group than in the patient group (11.21+/-6.98 vs. 4.46+/-6.90 ng/ml, p=0.010). Seven patients had a GH peak response of less than 3 ng/ml, compatible with the diagnosis of GH deficiency. Peak GH response after GHRH+arginine was significantly lower in the group of patients with GH peak of less than 3 ng/ml during ITT as compared to the group with GH peak of more than 3 ng/ml, and in all cases the diagnosis of GH deficiency was confirmed. Mean IGF-I level was not different between the patients and controls, as well as between patients with and without GH deficiency diagnosed by the stimulation tests. CONCLUSION: The incidence of GHD diagnosed by stimulation tests is high in patients cured of acromegaly.

Serum levels of bioactive IGF1 and physiological markers of ageing in healthy adults.

OBJECTIVE: Senescent changes in body composition and muscle strength are accompanied by reduced production of GH and IGF1, but the causal relationship remains elusive. We speculate that serum bioactive IGF1, measured by the IGF1 kinase receptor activation assay, is closer related to human physiological ageing than total IGF1 measured by immunoassay. DESIGN: We conducted a cross-sectional study in 150 adult males and females, between 20 and 70 years. After an overnight fasting, serum levels of bioactive IGF1, total IGF1 and IGF-binding protein 1 (IGFBP1) and IGFBP3 were assessed. Furthermore, body composition and muscle strength was measured. RESULTS: Total IGF1 levels were higher in females (P=0.048). Bioactive IGF1 were identical in males and females (P=0.31), decreasing with age. Total IGF1 tended to decrease more with age compared with bioactive IGF1 (-1.48 vs -0.89 percent/year, P=0.052). Total body fat (TBF) was lower and BMI was higher in males (P<0.001 and P=0.005), and both increased with age. Knee extension and elbow flexion force were higher in males (P=0.001 and P=0.001), but decreased with age in both genders. Total but not bioactive IGF1 was positively correlated to TBF, knee extension and muscle function in males. In multiple linear regression, only age predicted total IGF1, whereas age and IGFBP1 predicted bioactive IGF1. CONCLUSIONS: Bioactive IGF1 tends to decrease to a lesser extent than total IGF1 with age and was not correlated with measures of body composition or muscle strength. Therefore, levels of circulating bioactive IGF1 does not appear to be a better biomarker of physiological ageing than total IGF1.

Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery.

CONTEXT: Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial. OBJECTIVE: To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA). DESIGN AND METHODS: Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ)). RESULTS: Total and bioactive IGF1 (µg/l) levels were similar (total: 185 ± 10 (SA) versus 171 ± 8 (surgery) (P=0.28); bioactive: 1.9 ± 0.2 vs 1.9 ± 0.1 (P=0.70)). Suppression of total and free GH (µg/l) during OGTT was blunted in the SA group (total GH(nadir): 0.59 ± 0.08 (SA) versus 0.34 ± 0.06 (surgery) (P=0.01); free GH(nadir): 0.43 ± 0.06 vs 0.19 ± 0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02). CONCLUSIONS: i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

11Beta-HSD type 1 expression in human adipose tissue: impact of gender, obesity, and fat localization.

OBJECTIVE: Pre-receptor amplification of glucocorticoids is, in part, determined by the isoenzymes 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 and type 2, interconverting inert cortisone and active cortisol. Increased tissue activity of cortisol may play a part in features of the metabolic syndrome. Our objective was to compare 11beta-HSD1 gene expression in different fat depots (visceral, subcutaneous abdominal, and subcutaneous gluteal) in lean and obese men and women. RESEARCH METHODS AND PROCEDURES: A cross-sectional study design was used for healthy patients undergoing minor abdominal surgery (lean men, 10), minor gynecological surgery (lean woman, 10), or gastric banding operations (obese men, 10; and obese women, 10). Gene expressions of 11beta-HSD1 in adipose tissue samples were determined by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Lean women had lower 11beta-HSD1 gene expression in subcutaneous adipose tissue compared with men (62% lower, p < 0.01), whereas no significant difference was found between obese men and women. 11Beta-HSD1 mRNA in human adipose tissue was higher in obese subjects compared with lean subjects in both women and men and in both subcutaneous and visceral adipose tissue. No difference in mRNA expression of 11beta-HSD1 between visceral and subcutaneous adipose tissue or between subcutaneous adipose tissue from different depots was found. CONCLUSIONS: 11Beta-HSD1 in adipose tissue is increased in obesity in both women and men, and may contribute to the associated metabolic syndrome. As 11beta-HSD1 expression in lean women was found to be significantly lower than in lean males, the up-regulation associated with obesity may be relatively more devastating in women than in men, and may help explain the higher relative risk of cardiovascular disease in women suffering from the metabolic syndrome.