12-month effects of once-weekly sustained-release growth hormone treatment in adults with GH deficiency.

The weekly sustained-release recombinant human GH formulation LB03002, showed beneficial effects in GH-deficient (GHD) adults in a previous 26-week double-blind study. Prior studies of long-acting GH preparations in adults have only been conducted for 6 or 8 months, so the effects of longer-term use are unknown; this is important to address, as replacement is given for many years in GHD adults. This open-label, 26-week study extension evaluated longer-term safety and efficacy of LB03002 over 52 weeks in adults with GHD who had previously been randomized to GH, and provides additional safety and efficacy data over 26 weeks in the cohort who had previously been randomized to placebo. Of 147 adults with GHD who completed a preceding study, 136 patients continued in this open-label study to receive LB03002 over an additional 26 weeks. This represented a continuation of long-acting GH for 26 weeks in the cohort who took this medication in the prior study (LB03002 Throughout group), and describes the first use of long-acting GH in the cohort that was randomized to placebo in the prior study (Switched to LB03002 group). The LB03002 dose was adjusted according to serum insulin-like growth factor-I (IGF-I) levels. LB03002 treatment demonstrated mean significant decreases from baseline in fat mass (FM) for both 26 (Switched group, P = 0.001) and 52 weeks (Throughout group, P = 0.002) of 1.11 (1.95) kg and 1.06 (3.16) kg, respectively. Prolonged GH treatment was effective in sustaining the increase in lean body mass (LBM), serum IGF-I and IGFBP-3 levels achieved during the first 26 weeks. Long-term treatment with the sustained-release weekly GH preparation over both 26 and 52 weeks in adults with GHD demonstrated a sustained reduction of FM with a favorable safety profile. This study extends prior knowledge about long-acting GH because it reports the most prolonged treatment of adults with any long-acting GH preparation, thereby confirming the value and safety of such agents for long-term GH replacement.

Clinical experience with lanreotide for the treatment of acromegaly.

Acromegaly is a rare disease, characterized in adults by its distinctive appearance of facial dysmorphism and swollen fingers. It is caused by an overproduction of growth hormone (GH) in more than 99% of patients and in nearly all cases is due to a pituitary adenoma. If surgical resection of the adenoma is not effective, medical treatment is usually the next treatment option. The most commonly used medications are the somatostatin analogues octreotide and lanreotide. Lanreotide is a synthetic somatostatin analogue and is available as slow-release microparticle (every 7-14 days) and prolonged-release liquid (autogel, every 28-56 days) formulations. Lanreotide autogel is a supersaturated aqueous formulation for deep subcutaneous injection and is sold in a ready-to-use prefilled syringe. This ease of use allows self or partner administration at home. This article reviews the use of lanreotide in the treatment of acromegaly and its advantages and disadvantages compared with other somatostatin analogues.

A novel approach to the detection of acromegaly: accuracy of diagnosis by automatic face classification.

CONTEXT: The delay between onset of first symptoms and diagnosis of the acromegaly is 6-10 yr. Acromegaly causes typical changes of the face that might be recognized by face classification software. OBJECTIVE: The objective of the study was to assess classification accuracy of acromegaly by face-classification software. DESIGN: This was a diagnostic study. SETTING: The study was conducted in specialized care. PARTICIPANTS: Participants in the study included 57 patients with acromegaly (29 women, 28 men) and 60 sex- and age-matched controls. INTERVENTIONS: We took frontal and side photographs of the faces and grouped patients into subjects with mild, moderate, and severe facial features of acromegaly by overall impression. We then analyzed all pictures using computerized similarity analysis based on Gabor jets and geometry functions. We used the leave-one-out cross-validation method to classify subjects by the software. Additionally, all subjects were classified by visual impression by three acromegaly experts and three general internists. MAIN OUTCOME MEASURE: Classification accuracy by software, experts, and internists was measured. FINDINGS: The software correctly classified 71.9% of patients and 91.5% of controls. Classification accuracy for patients by visual analysis was 63.2 and 42.1% by experts and general internists, respectively. Classification accuracy for controls was 80.8 and 87.0% by experts and internists, respectively. The highest differences in accuracy between software and experts and internists were present for patients with mild acromegaly. CONCLUSIONS: Acromegaly can be detected by computer software using photographs of the face. Classification accuracy by software is higher than by medical experts or general internists, particularly in patients with mild features of acromegaly. This is a promising tool to help detecting acromegaly.

Effects of once-weekly sustained-release growth hormone: a double-blind, placebo-controlled study in adult growth hormone deficiency.

BACKGROUND: A sustained-release recombinant human GH formulation, LB03002, has been recently developed, with pharmacokinetics and pharmacodynamic activity appropriate for once-weekly administration. LB03002 is a long-acting GH that is administered once a week by s.c. injection. OBJECTIVE: This study evaluated efficacy and safety of LB03002 in adult patients with GH deficiency. PATIENTS AND METHODS: A total of 152 patients were randomized to receive LB03002 or placebo once weekly for 26 wk. Changes in body composition were evaluated from DXA (dual-energy x-ray absorptiometry). IGF-I was assessed at each study visit. Safety was assessed from adverse events, glucose homeostasis, and antibody development. RESULTS: IGF-I increased significantly (P < 0.001) with LB03002 and remained unchanged with placebo. Mean fat mass (FM) decreased by 1.052 kg [95% confidence interval (CI) = -1.614 to -0.491] in the LB03002 group vs. an increase of 0.570 kg (95% CI = -0.205-1.345) in the placebo group; treatment difference was 1.622 kg (95% CI = -2.527 to -0.717; P < 0.001). FM change was mainly due to decreased trunk fat. Least square mean treatment difference was 1.032 kg (95% CI = -1.560 to -0.515; P < 0.001). LBM (lean body mass) was significantly increased with LB03002 vs. placebo (least square mean difference was 1.393 kg; 95% CI = 0.614-2.171; P < 0.001). No concerning safety issues arose during the study. CONCLUSIONS: Weekly GH replacement with the sustained-release preparation LB03002 in adults significantly reduced FM over 6 months and was well tolerated.

Comparison of glucose and lipid metabolism and bone mineralization in patients with growth hormone deficiency with and without long-term growth hormone replacement.

The effects of long-term growth hormone (GH) substitution in pituitary-insufficient patients with GH deficiency (GHD-pats) on glucose and lipid metabolism and bone mineral density (BMD) have yet to be ascertained. We performed this cross-sectional study comparing GHD-pats with and without long-term GH substitution. We measured lipid parameters at baseline and glucose and insulin concentrations for 3 hours during oral glucose tolerance test in 52 GHD-pats (21 female and 31 male; median age, 51.5 years [27-82]). Twenty-two GHD-pats were on constant GH substitution (GH-Subs) for a median of 10 years (2-42 years). Thirty GHD-pats had not been substituted for at least 2 years (non-Subs). For analyses of beta-cell function, insulin resistance (IR), and sensitivity, homeostatic model assessment (HOMA)-beta , HOMA-IR, and insulin sensitivity index were used, respectively. Body composition and BMD were measured by dual-energy x-ray absorptiometry. Age and body mass index did not differ significantly between groups. Fasting glucose was significantly lower for GH-Subs than non-Subs (87 mg/dL [71-103] vs non-Subs 89 mg/dL [71-113], P < .05), whereas basal insulin did not differ significantly (10 muU/mL (4-42) vs non-Subs 10 microU/mL [4-63]). Glucose and insulin levels at 120 minutes as well as patients' area under the curve, C-peptide, hemoglobin A(1c), waist-hip ratio, HOMA-beta, HOMA-IR, insulin sensitivity index, lipid parameters, and BMD did not differ significantly; but total fat mass was significantly higher in non-Subs (37% [20%-52%] vs GH-sub 31% [13%-54%], P < .01). More non-Subs had abnormal glucose tolerance (19 [63%] vs GH-Subs 9 [41%]). Long-term GH substitution trends to beneficially influence fasting glucose and glucose tolerance, although differences are sparse. Growth hormone substitution alone does not seem to significantly impact on insulin sensitivity, lipid metabolism, and BMD in patients with pituitary insufficiency.

Chronic growth hormone excess is associated with increased aldosterone: a study in patients with acromegaly and in growth hormone transgenic mice.

Acromegaly is a disease characterized by chronic growth hormone (GH) excess. Since hypertension is a common finding in patients with acromegaly, interactions between GH and the renin-angiotensin-aldosterone system (RAAS) are under controversial debate. We examined GH, IGF-I, aldosterone, and renin in a well-defined group of acromegalic patients before and after cure by surgery. In addition, we analyzed the impact of chronic GH excess on the RAAS in mouse models over-expressing GH alone (G) or in combination with insulin-like growth factor-binding protein-2 (IGFBP-2; GB). Normalization of GH secretion after cure by surgery was accompanied by significant decreases of serum aldosterone in acromegalic patients (pre-op: 96.5 +/- 37.1 pg/mL, post-op: 41.3 +/- 28.2 pg/ mL; P < 0.001; n = 13), but renin concentrations were unaffected. In addition, aldosterone concentrations were positively correlated to GH levels (Spearman r = 0.39; P = 0.025; n = 26). To further study this association, we analysed two transgenic mouse models and found a similar relationship between GH and aldosterone in G mice, which showed about 3-fold elevated serum aldosterone levels in comparison to non-transgenic controls (males: 442 +/- 331 pg/mL vs. 151 +/- 84 pg/mL; P = 0.002; n > or = 12; females: 488 +/- 161 pg/mL vs. 108 +/- 125 pg/mL; P = 0.05; n > or = 4). Expression of aldosterone synthase was similar in adrenal glands of C and G mice. Aldosterone levels in G and GB mice of both genders were not different, indicating that the elevated aldosterone was due to GH excess and not caused by elevated IGF-I, which is known to be blocked by IGFBP-2 overexpression. Also in the mouse models, changes in aldosterone were independent from renin. In summary, we show that chronic GH excess is associated with increased aldosterone in humans and mice. GH-induced increases of aldosterone potentially contribute to the increased cardiovascular risk in acromegalic patients. The underlying mechanism is likely to be independent of renin, excess IGF-I, or adrenal aldosterone synthase expression.

Prevalence of mental disorders in acromegaly: a cross-sectional study in 81 acromegalic patients.

OBJECTIVE: Emotional and behavioural alterations have been described in acromegalic patients. However, the nature and psychopathological value of these changes remained unclear. We examined whether acromegalic patients have an increased prevalence of comorbid DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Version) mental disorders in comparison to subjects with or without chronic somatic disorders. DESIGN/PATIENTS: A cross-sectional study was conducted at the Max-Planck Institute of Psychiatry and the Ludwig-Maximilians-University Munich. Eighty-one acromegalic patients were enrolled. Control subjects with (n = 3281) and without chronic somatic (n = 430) disorders were drawn from a representative sample of the German adult general population as part of the Mental Health Supplement of the German Health Interview and Examination Survey. Lifetime and 12-month prevalences of DSM-IV mental disorders were assessed with face-to-face interviews using the standardized German computer-assisted version of the Composite International Diagnostic Interview. RESULTS: Acromegalic patients had increased lifetime rates of affective disorders of 34.6% compared to 21.4% in the group with chronic somatic disorders (OR = 2.0, 95% CI 1.2-3.2) and to 11.1% in the group without chronic somatic disorders (OR = 4.4, 95% CI 2.3-8.7). Affective disorders that occurred significantly more often than in the control groups began during the putative period of already present GH excess. Higher rates of DSM-IV mental disorders were reported in those patients with additional treatment after surgery. CONCLUSION: Acromegaly is associated with an increased prevalence and a specific pattern of affective disorders. Greater emphasis on diagnosing and treatment of mental disorders in acromegalic patients might improve the disease management.

Allelic variation of serotonin transporter function modulates the brain electrical response for error processing.

A functional length variation in the transcriptional control region of the serotonin transporter gene (5-HTTLPR) influences brain function, personality traits, and susceptibility to psychiatric disorders. Here we measured prefrontal brain function by means of event-related potentials during an error processing paradigm. Physiologically, occurrence of an error elicits two specific electrical responses in the prefrontal cortex, the early error related negativity (Ne/ERN) and the later occurring error positivity (Pe), reflecting different components of error processing. Healthy subjects with one or two copies of the low-activity 5-HTTLPR short variant showed significantly higher amplitudes of the Ne/ERN and a trend to higher amplitudes of the Pe as compared to age- and gender-matched individuals homozygous for the long allele. Performance measures and latencies of these ERP-components did not differ between groups. These results indicate that the 5-HTTLPR short variant is associated with enhanced responsiveness of the brain and further supports the notion that prefrontal brain function is influenced by allelic variation in serotonin transporter function.