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Christian J Strasburger

The quantitative determination of human growth hormone (hGH) levels in serum has been of interest since even before the advent of radioimmunoassay in trying to enhance our understanding of growth-related disorders, such as GH deficiency associated with short stature in children or acromegaly in adults. Historically, different methodological approaches have been chosen. Competitive immunoassays were followed by sandwichtype immunometric assays; initially all assays used polyclonal antibodies generated by immunization with pituitary-extracted hGH. Since the introduction of the hybridoma technique, increasing numbers of immunoassays for quantitative GH determination make use of monoclonal antibodies, most of which are raised against recombinant 22-kD GH.

The 22-kD form of GH, comprising the full length of 191 amino acids and encoded by the pituitary-transcribed GH gene, represents the major form of hGH in circulation and in the pituitary. Therefore, all attempts at quantitative determination of hGH levels have aimed at this molecular isoform. The 22-kD

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Christian J Strasburger and Wieland Kiess

In the 1960s pharmacotherapy with pituitary-derived human growth hormone (GH) preparations was introduced into clinics for the treatment of children with severely impaired longitudinal bone growth (1). Initially, the generally accepted route of GH administration was deep intramuscular injections. It was not until the advent of recombinant growth hormone preparations in the 1980s that subcutaneous injection of GH proved to be at least equally effective and was propagated widely (2). The less traumatic subcutaneous injection then facilitated investigation of effectiveness as a function of number of injections per week. With respect to the promotion of longitudinal bone growth in children and adolescents, daily subcutaneous injection was shown to be more effective than administration of the same weekly dose by injection thrice weekly. Extrapolation of these findings promoted further studies in animals and humans that unanimously demonstrated the superior effectivity of continuous GH infusion as compared to administration of the same

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Christoph J Auernhammer and Christian J Strasburger

Auernhammer CJ, Strasburger CJ. Effects of growth hormone and insulin-like growth factor I on the immune system. Eur J Endocrinol 1995;133:635–45. ISSN 0804–4643

Growth hormone-releasing hormone (GHRH). growth hormone (GH), prolactin (PRL) and insulin-like growth factor I (IGF-I) are synthesized and secreted by various immunocompetent cells. In addition, GHRH, GH, PRL and IGF-I receptors are expressed on immune cells. Growth hormone, PRL and IGF-I stimulate the proliferation of immunocompetent cells and modulate humoral and cellular immune functions, i.e. immunoglobuline secretion of B cells, thymulin secretion of thymic epithelial cells, natural killer cell activity, phagocytosis, oxidative burst and killing capacity of neutrophils and macrophages. No clinically significant cellular or humoral immunodeficiency has been found in GH-deficient patients. However, several immunological parameters and functions are altered in GH-deficient patients when compared to normal controls. The data available to date indicate that endocrine and pleiotropic para- and autocrine mechanisms of action are involved in a neuropeptide immune network, including GH PRL and IGF-I as modulators of immune function.

Christian J Strasburger, Medizinische Klinik, Klinikum Innenstadt der LMU, Ziemssenstr. 1, 80336 Munich, Germany

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Tina Kienitz, Marcus Quinkler, Christian J Strasburger and Manfred Ventz

Objective: TSH-secreting pituitary tumors (TSH-omas) are a rare cause of hyperthyroidism and account for <1% of all pituitary adenomas. Failure to recognize the presence of a TSH-oma may result in dramatic consequences such as thyroid ablation that may cause further growth in pituitary tumor. The primary goal of the treatment of TSH-omas is to remove the pituitary tumor. Medical treatment includes dopaminergic agonists or somatostatin analogs.

Methods and results: We report five cases of TSH-oma diagnosed between 1997 and 2006 and review the literature. All the patients are females with an age range from 54 to 65 years at diagnosis. Four of the five patients had at least one event of thyroid surgery due to goiter or nodule of unknown dignity. Three of the five patients had a stroke before the diagnosis of TSH-oma, probably due to hypertension, or smoking and contraceptive treatment. One patient with invasive tumor growth received stereotactic radiotherapy (and developed panhypopituitarism after operation), another patient received somatostatin analogs preoperatively and successfully underwent transsphenoidal operation. Three of the five patients received dopaminergic agonists (bromocriptine 5 mg daily or cabergoline 0.5–0.75 mg per week), because they refused surgical therapy or the tumor was stable under dopaminergic therapy. All patients have been followed-up for 2.5–8 years. A normalization of circulating thyroid hormone levels was achieved in all patients. The patient who underwent operation shows no recurrence of the disease. The other patients have a stable pituitary mass without signs of growth.

Conclusion: We report the successful long-term treatment of TSH-omas with different therapies.

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Timo Deutschbein, Martin Bidlingmaier, Jochen Schopohl, Christian J Strasburger and Stephan Petersenn

Context

Adult growth hormone (GH) deficiency (GHD) is diagnosed by provocative testing of GH secretion.

Objective

To improve the diagnostic accuracy of GH-releasing hormone (GHRH) plus arginine (GARG) testing, we evaluated the influence of age, BMI and sex and established normative data for an automatic immunoassay specifically measuring 22 kDa human GH.

Design/setting

Prospective multicenter study.

Participants

Eighty-seven patients with hypothalamic–pituitary disease and 200 healthy controls. Patients were classified according to the number of pituitary hormone deficiencies (PHD). GHD was assumed when ≥2 PHD (in addition to GH) were present (n = 51); 36 patients with <2 PHD were considered GH sufficient (GHS). ROC analysis identified cutoffs with ≥95% specificity for GHD. Controls were prospectively stratified for sex, age and BMI.

Interventions

All participants received GHRH and l-arginine.

Main outcome measures

GH was measured by immunoassay (iSYS, IDS).

Results

In controls, multiple stepwise regression analysis showed that BMI (21%, P < 0.0001), sex (20%, P < 0.0001) and age (5%, P < 0.001), accounted for 46% of GH peak level variability during GARG. Comparison of peak GH during GARG (GHD vs GHS + controls) revealed an overall cutoff of 3.9 ng/mL (sensitivity 86%, specificity 95%). After adjustment for BMI and sex, optimal cutoffs (male vs female) were 6.5 vs 9.7 ng/mL in lean, 3.5 vs 8.5 ng/mL in overweight and 2.2 vs 4.4 ng/mL in obese subjects respectively.

Conclusion

BMI and sex account for most of the variability of peak GH levels during GARG. Consequently, diagnostic accuracy of the GARG test is significantly improved by use of adjusted cutoffs.

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Katherine M Morrison, Martin Bidlingmaier, Simone Stadler, Zida Wu, Lars Skriver and Christian J Strasburger

Objective: The usefulness of measuring the GH-dependent acid-labile subunit (ALS) in the management of GH deficiency (GHD) and acromegaly remains in question and is investigated in this study, comparing several different immunoassays for ALS.

Method: We compared the diagnostic accuracy of a commercially available polyclonal Ab-based ELISA with SDS pre-treatment (SDS-ELISA) with a monoclonal Ab-based immunofluorometric assay, using two unfolding methods (urea (UREA) and Glycine-HCl (Gly)). The corresponding molecular weight (MW) of ALS and IGFBP-3 immunoreactivity was determined. The clinical usefulness of each assay was examined in adult GH disorders.

Results: ALS was lower in GHD and higher in acromegaly using all assays. In GHD, UREA had higher sensitivity and specificity than SDS-ELISA (59 and 69% versus 41 and 51% respectively). In acromegaly, sensitivity and specificity was 94 and 87% for UREA, 81 and 36% for Gly, and 44 and 44% for SDS-ELISA. After UREA, immunoreactivity for ALS and IGFBP-3 eluted at their predicted free MW using size-exclusion chromatography, whereas ALS immunoreactivity in SDS (300–600 kDa) and Gly (250–500 kDa) was at a high apparent MW consistent with aggregation.

Conclusion: The diagnostic accuracy of ALS varies with assay choice and pre-treatment modality. UREA, which results in migration of ALS at the expected MW on a sizing column, has the highest specificity and sensitivity. Thus, if measured in an assay in which ALS is unfolded without aggregation, ALS is a clinically highly useful parameter for the assessment of GH.

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Michael Droste, Julia Domberg, Michael Buchfelder, Klaus Mann, Anja Schwanke, Günter Stalla and Christian J Strasburger

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Christian J Strasburger, Anders Mattsson, Patrick Wilton, Ferah Aydin, Judith Hey-Hadavi and Beverly M K Biller

Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with pegvisomant, ‘Combo SSA’ 768 patients (38%); DA combined with pegvisomant, ‘Combo DA’ 123 (6%); pegvisomant monotherapy, ‘Peg mono’ 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries.

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Michael Droste, Julia Domberg, Michael Buchfelder, Klaus Mann, Anja Schwanke, Günter Stalla and Christian J Strasburger

Objective

Acromegaly is associated with an increased prevalence of glucose metabolism disorders. Clinically confirmed diabetes mellitus is observed in approximately one quarter of all patients with acromegaly and is known to have a worse prognosis in these patients.

Design

Of 514 acromegalic patients treated with pegvisomant and recorded in the German Cohort of ACROSTUDY, 147 had concomitant diabetes mellitus. We analysed these patients in an observational study and compared patients with and without concomitant diabetes.

Results

Under treatment with pegvisomant, patients with diabetes mellitus rarely achieved normalisation (64% in the diabetic cohort vs 75% in the non-diabetic cohort, P=0.04) for IGF1. Diabetic patients normalised for IGF1 required higher pegvisomant doses (18.9 vs 15.5 mg pegvisomant/day, P<0.01). Furthermore, those diabetic patients requiring insulin therapy showed a tendency towards requiring even higher pegvisomant doses to normalise IGF1 values than diabetic patients receiving only oral treatment (22.8 vs 17.2 mg pegvisomant/day, P=0.11).

Conclusions

Hence, notable interdependences between the acromegaly, the glucose metabolism of predisposed patients and their treatment with pegvisomant were observed. Our data support recent findings suggesting that intra-portal insulin levels determine the GH receptor expression in the liver underlined by the fact that patients with concomitant diabetes mellitus, in particular those receiving insulin therapy, require higher pegvisomant doses to normalise IGF1. It is therefore important to analyse various therapy modalities to find out whether they influence the associated diabetes mellitus and/or whether the presence of diabetes mellitus influences the treatment results of an acromegaly therapy.

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Annamaria Colao, Rosario Pivonello, Renata S Auriemma, Maria Cristina De Martino, Martin Bidlingmaier, Francesco Briganti, Fabio Tortora, Pia Burman, Ione A Kourides, Christian J Strasburger and Gaetano Lombardi

Objective: We aimed to investigate the efficacy of pegvisomant in patients with acromegaly resistant to long-term (≧ 24-month), high-dose treatment with octreotide-LAR (40 mg/month) or lanreotide (120 mg/month).

Design: This was an open, prospective study.

Subjects and Methods: We studied 16 patients with acromegaly (nine women; aged 28–61 years). The main outcome measures were IGF-I levels, blood pressure, glucose tolerance and safety (liver function and tumor size). Pegvisomant was given at doses of 10–40 mg s.c. daily. Dose titration was performed every month by IGF-I assay.

Results: Three patients spontaneously stopped pegvisomant treatment after 6–9 months because of poor compliance; from the measurement of serum pegvisomant, another patient was found not to inject herself properly. After 6 months, IGF-I levels decreased by 63 ± 19% (767.8 ± 152.9 vs 299.8 ± 162.9 μg/l, P < 0.0001, t-test); serum IGF-I levels normalized in 57%. After 12 months, IGF-I levels normalized in nine (75%) patients and were reduced by over 50% in another three (25%). The mean tumor volume remained stable during the study (1198 ± 1234 vs 1196 ± 1351 mm3, P = 0.37): it did not change ( ± 25% vs basal) in nine patients, increased by 39.4% and 40.8% in two and decreased by 30.8–46.5% in four. The total/high-density lipoprotein (HDL):cholesterol ratio (from 4.4 ± 1.0 to 3.7 ± 0.6, P= 0.0012), glucose levels (from 5.6 ± 1.2 to 4.4 ± 1.4 mmol/l, P = 0.026), insulin levels (from 12.4 ± 6.7 to 8.1 ± 3.0 mUl/l, P = 0.0023) and homeostasis model assessment (HOMA) index (from 3.4 ± 2.1 to 1.9 ± 1.0, P = 0.0017) decreased.

Conclusions: Treatment for 12 months with pegvisomant normalized IGF-I levels, and improved cardiovascular risk parameters and insulin sensitivity in patients with acromegaly resistant to long-term, high-dose treatment with somatostatin analogs. The tolerance of treatment was good.