Abstract. We studied the metabolic clearance rate (MCR) serum half-time (t½) and apparent distribution space (DS) of unlabelled, authentic, biosynthetic human growth hormone (B-hGH) in 9 GH-deficient patients by means of the constant iv infusion to equilibrium technique. B-hGH was infused for 3 h at a rate of 33 ng · kg−1 · min−1 after which the disappearance from serum of GH was followed for 1 h. The mean ± sem values for MCR, t½ and DS were: 2.3 ± 0.6 ml · kg−1 · min−1, 21.1 ± 1.7 min and 67.6 ± 14.6 ml/kg, respectively. The disappearance of GH was monoexponential for the first 30 min, during which 75% of the GH had been cleared. The disappearance rate during the last 30 min of the observation period was somewhat lower, still approximately 90% of the GH had been eliminated after 60 min.
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J. O. L. Jørgensen, A. Flyvbjerg, and J. S. Christiansen
Sebastian J Neggers, John J Kopchick, Jens O L Jørgensen, and Aart J van der Lely
Medical treatment of acromegaly with long-acting somatostatin analogs (LA-SMSA) and the GH receptor antagonist, pegvisomant (PEGV), has made it possible to achieve normal serum IGF1 concentrations in a majority of patients with acromegaly. These two compounds, however, impact the GH–IGF1 axis differently, which challenges the traditional biochemical assessment of the therapeutic response. We postulate that LA-SMSA in certain patients normalizes serum IGF1 levels in the presence of elevated GH actions in extra-hepatic tissues. This may result in persistent disease activity for which we propose the term extra-hepatic acromegaly. PEGV, on the other hand, blocks systemic GH actions, which are not necessarily reliably reflected by serum IGF1 levels, and this treatment causes a further elevation of serum GH levels. Medical treatment is therefore difficult to monitor with the traditional biomarkers. Moreover, the different modes of actions of LA-SMSA and PEGV make it attractive to use the two drugs in combination. We believe that it is time to challenge the existing concepts of treatment and monitoring of patients with acromegaly.
J. O. L. Jørgensen, A. Flyvbjerg, T. Lauritzen, H. Ørskov, and J. S. Christiansen
Abstract. The aim of the present study was to look further into the question of local degradation of sc injected human GH in GH deficient patients. A comparison was made of serum GH levels after constant iv and sc infusion of the same amount of GH (33 ng· kg−1·min−1) in the same 9 GH deficient patients. A 3-h lag period was interposed between the iv and the sc infusion. Iv infusion was continued for 3 h. All 9 subjects subsequently received sc infusion for 19 h and five of them continued for additionally 24 h. The mean steady state serum GH level in the nine patients was 23.1 ± 5.1 μg/l after iv and 6.8 ± μg/l after sc administration (P < 0.01). Extension of the sc infusion period in 4 of the subjects did not significantly alter the serum GH level (P > 0.15), implying that a steady state was reached. The GH in the infusion system was stable throughout a 24-h period. We therefore conclude that sc injected GH is degraded locally to a substantial extent.
N. Møller, J. O. L. Jørgensen, J. Møller, L. Ørskov, N. Pørksen, K. G. M. M. Alberti, and O. Schmitz
There is evidence that hyperketonemia in insulin-dependent diabetes may be aggravated by a decreased disposal rate for ketone bodies. To test the hypothesis that this decrease may be induced by concomitant hyperglycemia through substrate competition at the acetyl-CoA level, 5 young insulin-dependent diabetic subjects received at 2-h iv infusion of 0.9 mmol 3-hydroxybutyrate · kg−1 · h−1 at clamped 1. euglycemia (5 mmol/l) and 2. hyperglycemia (11 mmol/l) on separate occasions. To ensure similar metabolic conditions, a low-dose hyperinsulinemic euglycemic clamp was performed during the 5 h preceding the actual studies. Substrate fluxes in muscle were assessed through the forearm technique. The glucose infusion rate was 4.9 and 2.9 mg· kg−1·min−1, and the forearm arteriovenous difference for glucose was 0.72 during hyperglycemia and 0.39 mmol/l (p<0.05). during euglycemia. Hyperglycemia did not affect circulating levels of free insulin, glucagon, nonesterified fatty acids, 3-hydroxybutyrate (hyperglycemia: 665, euglycemia: 770 μmol/l, p>0.05) or acetoacetate, nor forearm uptake of 3-hydroxybutyrat (hyperglycemia, 152, euglycemia: 168 μmol/l, p>0.05). In conclusion, our results do not suggest any inhibitory role for hyperglycemia in the disposal of ketone bodies. In as much as extrapolation from the present well insulinized state is appropriate, the data indicate that alternative mechanisms may be involved in the observed impairment of ketone body clearance in hyperketonemic insulin-dependent diabetic patients.
S E Franck, A J van der Lely, P J D Delhanty, J O L Jørgensen, and S J C M M Neggers
Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear.
To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment.
Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (>1.2 upper limit of normal; n=112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients.
D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy–Weinberg equilibrium (P=0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (P=0.337) or PEGV serum levels (P=0.433) was observed between the two groups. However, adenoma size decreased significantly (>20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (P=0.034, OR: 4.6 (CI: 1.1–18.9)).
GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size.
O M Dekkers, V Ehrenstein, M Bengtsen, D Kormendine Farkas, A M Pereira, H T Sørensen, and J O L Jørgensen
To enhance the precision of the risk estimate for breast cancer in hyperprolactinemia patients by collecting more data and pooling our results with available data from former studies in a meta-analysis.
Population-based cohort study and meta-analysis of the literature.
Using nationwide registries, we identified all patients with a first-time diagnosis of hyperprolactinemia during 1994–2012 including those with a new breast cancer diagnoses after the start of follow-up. We calculated standardised incidence ratios (SIRs) as a measure of relative risk (RR) using national cancer incidence rates. We performed a meta-analysis, combining data from our study with data in the existing literature.
We identified 2457 patients with hyperprolactinemia and 20 breast cancer cases during 19 411 person-years of follow-up, yielding a SIR of 0.99 (95% CI 0.60–1.52). Data from two additional cohort studies were retrieved and analyzed. When the three risk estimates were pooled, the combined RR was 1.04 (95% CI 0.75–1.43).
We found no increased risk of breast cancer among patients with hyperprolactinemia.
J. O. L. Jørgensen, A. Flyvbjerg, J. Dinesen, H. Lund, K. G. M. M. Alberti, H. Ørskov, and J. S. Christiansen
Abstract. In a double-blind cross-over study we compared pituitary and methionine-free biosynthetic human growth hormone (P-hGH and B-hGH) with respect to pharmacokinetics and short-term metabolic effects in 9 hypopituitary children. They treated themselves for 4 weeks with 2 IU sc daily at 20.00 h. After admittance to hospital 2 IU was given: im the first day, and sc the second. They then switched over to the alternative preparation. The serum profiles of B- and P-hGH were identical. Comparing im and sc adsorption, the latter was slower and resulted in smaller areas under the curves, indicating greater local degradation.
Both preparations caused identical increases in somatomedin-C, but slightly more sustained after sc injection. Plasma glucose, plasma glucagon, and serum insulin fluctuated within normal ranges. The glucose profile pointed at a modest anti-insulin effect of hGH when given in the morning. The concentration in the blood of lactate, alanine, glycerol and B-OH-butyrate, and in serum of triglyceride, cholesterol and carbamide revealed no abnormalities with either hGH preparation. Finally, no development of anti-GH or E. coli polypeptide antibodies was seen. In conclusion, the pharmacokinetics and short-term metabolic effects of B-hGH and P-hGH were identical.
E T Vestergaard, T K Hansen, S Nielsen, N Moller, J S Christiansen, and J O L Jorgensen
Objective: The regulation and function of systemic ghrelin levels appear to be associated with food intake and energy balance rather than GH. Since GH, in turn, acutely induces lipolysis and insulin resistance in skeletal muscle, we aimed to study the isolated and combined effects of GH, free fatty acids (FFAs) and insulin sensitivity on circulating ghrelin levels in human subjects.
Design: Seven GH-deficient patients (aged 37 ± 4 years (mean ± s.e.)) were studied on four occasions in a 2 × 2 factorial design with and without GH substitution and with and without administration of acipimox, which lowers FFA levels by inhibition of the hormone-sensitive lipase, in the basal state and during a hyperinsulinemic euglycemic clamp.
Results: Serum FFA levels decreased with acipimox administration irrespective of GH status. The GH-induced reduction in insulin sensitivity was countered by acipimox. Fasting ghrelin levels decreased insignificantly during GH administration alone, but were reduced by 33% during co-administration of GH and acipimox (Aci) (in ng/l): 860 ± 120 (−GH − Aci), 711 ± 130 (−GH + Aci), 806 ± 130 (+GH − Aci), 574 ± 129 (+GH + Aci), P < 0.01. The clamp was associated with a further, moderate lowering of ghrelin. GH and acipimox induced a reciprocal 25% increase in serum leptin levels (μg/l): 11.2 ± 4.4 (−GH − Aci), 11.7 ± 4.4 (−GH + Aci), 11.5 ± 4.4 (+GH − Aci), 13.9 ± 4.2 (+GH + Aci), P = 0.005.
Conclusion: Our data suggest that antilipolysis via suppression of the hormone-sensitive lipase in combination with GH administration is associated with significant and reciprocal changes in ghrelin and leptin.
A Muhammad, A J van der Lely, R D O’Connor, P J Delhanty, J Dal, A H Dallenga, R A Feelders, J A M J L Janssen, J O L Jorgensen, and S J C M M Neggers
Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients’ comfort, but the efficacy is unknown.
To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV.
Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly.
Subjects and methods
The study included 15 subjects (eight males), with a median age of 58 years (range 35 – 80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels.
After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30 – 0.84) to 0.83 × ULN (0.30 – 1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30 – 80) mg to 80 (50 – 120) mg.
Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.
A Luger, L H A Broersen, N R Biermasz, B M K Biller, M Buchfelder, P Chanson, J O L Jorgensen, F Kelestimur, S Llahana, D Maiter, G Mintziori, F Petraglia, R Verkauskiene, S M Webb, and O M Dekkers
Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.