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Bioavailability and bioactivity of three different doses of nasal growth hormone (GH) administered to GH-deficient patients: comparison with intravenous and subcutaneous administration

Torben Laursen, Birgitte Grandjean, Jens OL Jørgensen, and Jens S Christiansen

Laursen T, Grandjean B, Jørgensen JOL, Christiansen JS. Bioavailability and bioactivity of three different doses of nasal growth hormone (GH) administered to GH-deflcient patients: comparison with intravenous and subcutaneous administration. Eur J Endocrinol 1996;135:309–15. ISSN 0804–4643

The current mode of growth hormone (GH) replacement therapy is daily subcutaneous (sc) injections given in the evening. This schedule is unable to mimic the endogenous pulsatile pattern of GH secretion, which might be of importance for the induction of growth and other GH actions. The present study was conducted in order to study the pharmacokinetics of different doses of GH following intranasal (IN) administration and the biological activity of GH after IN administration as compared with sc and intravenous (iv) delivery. Sixteen GH-deficient patients were studied on five different occasions. On three occasions GH was administered intranasally in doses of 0.05, 0.10 and 0.20IU/kg, using didecanoyl-l-α-phosphatidylcholine as an enhancer. On the other two occasions the patients received an sc injection (0.10IU/kg) and an iv injection (0.015IU/kg) of GH, respectively. The nasal doses and the sc injection were given in random order in a crossover design. In a double-blinded manner the subjects received the three nasal doses as one puff in each nostril. The patients received no GH treatment between the five studies or during the last week before the start of each study. Intravenous administration produced a short-lived serum GH peak value of 128.12 ± 6.71 μg/l. Peak levels were 13.98±1.63 μg/l after sc injection and 3.26±0.38. 7.07±0.80 and 8.37± 1.31 μg/l, respectively, after the three nasal doses. The peak values of the 0.05 and the 0.20IU/kg nasal doses were significantly different (p = 0.007). The mean levels obtained by the low nasal dose were significantly lower than those obtained with the medium (p < 0.001) and the high dose (p < 0.001). while there was no significant difference between the medium and the high doses. The absolute bioavailability of GH following sc relative to iv administration was 49.5%. The bioavailabilities of the nasal doses were: 7.8% (0.05 IU), 8.9% (0.10 IU) and 3.8% (0.20 IU). Serum insulin-like growth factor I (IGF-I) levels increased significantly after sc administration only. Mean levels were significantly higher after sc administration as compared with the iv and all three nasal does (p < 0.001). Serum IGF binding protein 3 (IGFBP-3) levels remained unchanged on all five occasions. Mean serum IGFBP-1 levels were significantly lower after sc GH injection than after administration of the iv (p < 0.001) and the three nasal doses (p < 0.005). Subcutaneous GH administration resulted in significantly higher levels of serum insulin and blood glucose (p < 0.001). In conclusion, the bioavailability of nasal GH was low (3.8–8.9%). An iv bolus injection of, on average, 1 IU of GH induced no metabolic response. Only sc GH administration induced increased levels of IGF-I, insulin and glucose. These data reveal that a closer imitation of the physiological GH pulses than achieved by sc GH administration is of limited importance for the induction of a metabolic response to GH.

Torben Laursen, Medical Department M (Diabetes & Endocrinology), Aarhus Kommunehospital, DK-8000 Aarhus C. Denmark

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Nationwide trends in surgery and radioiodine treatment for benign thyroid disease during iodization of salt

Charlotte Cerqueira, Nils Knudsen, Lars Ovesen, Peter Laurberg, Hans Perrild, Lone B Rasmussen, and Torben Jørgensen

Objective

Iodization of salt was introduced in Denmark in 1998 because of mild-to-moderate iodine deficiency (ID). The aim of this study was to analyze the utilization rate of surgery and radioiodine therapy for benign thyroid disorders before and after the introduction of iodization, and to study a possible association between the changes and the raised iodine intake.

Design

A nationwide register study.

Methods

Information on operations and radioiodine treatments for benign thyroid disorders was extracted from nationwide registers in the years 1990 to 2007. Treatment rates are presented for surgery and for radioiodine separately, and as a combined rate, both nationwide and split by the regions of prior mild and moderate ID.

Results

A total of 65 605 treatments were identified: 26 456 operations and 39 149 radioiodine treatments. In the first years of iodization (1998–2000; rate ratio 2000/1997), the combined treatment rate increased with 2.5% (95% confidence interval (CI): −1.8–7.1). Split by prior ID level, the increase was seen in the region of moderate ID, but a decrease was seen in the region of mild ID. After 2000, the combined rate decreased, and ended up being 11.1% (95% CI: 7.1–15.0) lower in 2007 than before iodization (rate ratio 2007/1997). The changes were primarily due to changes in the use of radioiodine therapy as the surgery rates remained almost constant.

Conclusions

Iodization seemed to be associated with a temporary increase in the utilization rate of surgery and radioiodine therapy in the region of prior moderate ID, probably as a result of treatment of iodine-induced hyperthyroidism, but the rates ended up being lower than before iodization.

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Effects of octreotide on insulin-like growth factor I and metabolic indices in growth hormone-treated growth hormone-deficient patients

Torben Laursen, Jens OL Jorgensen, Hans Ørskov, Jens Møller, Alan G Harris, and Jens S Christiansen

Animal studies have demonstrated that in addition to inhibiting growth hormone (GH) secretion octreotide inhibits in a direct manner hepatic or peripheral insulin-like growth factor I (IGF-I) generation. To test this hypothesis in humans we studied ten GH-deficient patients with frequent blood sampling during 38 h on two occasions. Regular GH therapy was discontinued 72 h prior to each study period. At the start of each study a subcutaneous (sc) injection of GH (3 IU/m2) was given (at 18.00 h). In a single-blinded crossover design, patients received a continuous sc infusion of either octerotide (200 μg/24 h) or placebo (saline). The pharmacokinetics of GH were similar on the two occasions. The area under the curve±sem of serum GH was 142.5±53.6 μg·l−1·h−1 (octreotide) and 144.8±41.8 μg·l−1·h−1 (placebo), (p=0.73); Cmax (μg/l) was 12.5±1.47 (octreotide) and 12.8±1.42 (placebo) (p=0.83), and Tmax (h) was 6.1±0.97 (octreotide) and 5.2±0.65 (placebo) (p=0.49). Growth hormone administration was associated with an increase in serum IGF-I (μg/l), which was identical during the two studies, from 85.3±19.4 to 174.25±30.3 for octreotide and from 97.0±26.4 to 158.8±28.2 for placebo. Mean IGF-I levels (μg/l) were 138.2±25.1 (octreotide) and 134.5±28.6 (placebo) (p=0.78). Similarly, the increase in IGF binding protein 3 (IGFBP-3) levels was identical. Mean IGFBP-3 levels (μg/l) were 2303±323 (octreotide) and 2200±361 (placebo) (p=0.25). Mean insulin levels were significantly lower during octreotide treatment (39.9±17.9 mU/l) than during placebo (59.7±17.8 mU/l) (p<0.05). Mean blood glucose levels were elevated significantly during octreotide infusion (5.98±0.23 mmol/l for octreotide and 5.07±0.16 mmol/l for placebo; p=0.001). Glucagon levels decreased non-significantly (p=0.07) and IGFBP-1 levels tended to increase during infusion of octreotide although not significantly (p=0.41). Levels of the lipid intermediates were identical on the two occasions. Alanine and lactate levels were significantly increased during octreotide infusion. Mean levels of blood alanine (μmol/l) were 470.8±24.2 (octreotide) and 360.1±17.8 (placebo) (p<0.02). Mean levels of blood lactate were 1038±81.0 (octreotide) and 894.4±73.8 (placebo) (p<0.04). We conclude that short-term continuous sc infusion of octreotide has no direct effect on the generation of IGF-I or the pharmacokinetics of exogenous GH in GH-deficient man.

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Variation in the gene encoding Krüppel-like factor 7 influences body fat: studies of 14 818 Danes

Dorit P Zobel, Camilla H Andreasen, Kristoffer S Burgdorf, Ehm A Andersson, Annelli Sandbæk, Torsten Lauritzen, Knut Borch-Johnsen, Torben Jørgensen, Shiro Maeda, Yusuke Nakamura, Hans Eiberg, Oluf Pedersen, and Torben Hansen

The authors and journal apologize for an error in the above paper above which appeared in 160 (4) 603–609. The twelfth author's name should have appeared as Oluf Pedersen, as shown correctly above.

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Studies of association between LPIN1 variants and common metabolic phenotypes among 17 538 Danes

Kristoffer Sølvsten Burgdorf, Camilla Helene Sandholt, Thomas Sparsø, Gitte Andersen, Daniel R Witte, Torben Jørgensen, Anelli Sandbæk, Torsten Lauritzen, Thorkild I A Sørensen, Sten Madsbad, Torben Hansen, and Oluf Pedersen

Objective

Lipin-1, encoded by LPIN1, is expressed in the major metabolically active tissues. Decreased expression of lipin-1 in adipose tissue correlates with increased insulin resistance, and tagging of the LPIN1 locus has shown that rs33997857, rs6744682, and rs6708316 associate with metabolic phenotypes, specifically body mass index (BMI) and fasting serum lipid levels, both on the individual single-nucleotide polymorphism level and with a three-marker haplotype. Our aim was to validate the reported findings in the Danish population.

Design

In the present study, variants were analyzed in LPIN1 using case–control studies, haplotype analyses, and quantitative trait analyses in a population of 17 538 Danes.

Methods

The three LPIN1 variants were genotyped in 17 538 Danes from four study populations of middle-aged people. This provided us with a statistical power >99% to replicate previous findings. Variants were analyzed individually and in haplotype combinations in studies of quantitative metabolic traits and in case–control studies.

Results

None of the three variants were associated with the examined quantitative traits including BMI, waist circumference, blood pressure, fasting serum lipid concentrations, or plasma glucose or serum insulin concentrations in the fasting state and following an oral glucose tolerance test. Haplotypes were tested for association with quantitative traits; however, only nominal association with blood pressure (P=0.04) and waist circumference (P=0.04) was observed. In case–control studies, no association was found for individual variants or the three-marker haplotype.

Conclusion

LPIN1 rs33997857, rs6744682, and rs6708316 did not associate with type 2 diabetes, obesity, or related quantitative metabolic phenotypes in the Danish population examined.

Free access

Variation in the gene encoding Krüppel-like factor 7 influences body fat: studies of 14 818 Danes

Dorit P Zobel, Camilla H Andreasen, Kristoffer S Burgdorf, Ehm A Andersson, Annelli Sandbæk, Torsten Lauritzen, Knut Borch-Johnsen, Torben Jørgensen, Shiro Maeda, Yusuke Nakamura, Hans Eiberg, Oluf Pederse, and Torben Hansen

Objective

KLF7 encodes Krüppel-like factor (KLF) 7, a member of the KLF family of transcription factors, initially shown to play important roles in cellular development and differentiation, and reported to be specifically involved in adipogenesis. Several single nucleotide polymorphisms (SNPs) have been identified in KLF7, of which the A-allele of rs2302870 has been associated with type 2 diabetes in a Japanese population; however, a possible association of KLF7 SNPs with obesity has not been investigated. We aimed to identify variation in the putative promoter region, the coding regions, exon/intron boundaries, and 3′-UTR of KLF7, and to examine identified variants in relation to obesity, type 2 diabetes, and related quantitative traits in Danish individuals.

Methods

Identified variants were investigated for association with type 2 diabetes in 8777 individuals and with obesity in 14 818 individuals.

Results

We identified four common SNPs in low pairwise linkage disequilibrium; three in the putative promoter region (−1119 G>A, −963 C>A (rs7568369), and −614 G>A) and IVS2+35092 A>C (rs2302870). We failed to confirm an association between rs2302870 and type 2 diabetes. Neither was rs7568369 associated with type 2 diabetes; however, the minor A-allele of rs7568369 protected against obesity (OR=0.90 (0.84–0.96), P=0.001) and in studies of quantitative traits (n=5,535) the variant associated with decreased body mass index (P=0.002) and waist circumference (P=0.003). The −1119 G>A and −614 G>A variants were not associated with obesity or type 2 diabetes.

Conclusion

We identified a novel association between the minor A-allele of KLF7 rs7568369 and protection against obesity in the Danish population.

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Thyroglobulin as a marker of iodine nutrition status in the general population

Pernille Vejbjerg, Nils Knudsen, Hans Perrild, Peter Laurberg, Allan Carlé, Inge Bülow Pedersen, Lone B Rasmussen, Lars Ovesen, and Torben Jørgensen

Objective

The iodine status of a population is traditionally evaluated by either urinary iodine (UI) excretion or by some measure of thyroid volume and the prevalence of goitre. In this prospective study of a mandatory iodization programme, we aimed to evaluate serum thyroglobulin (Tg) as a marker of iodine status in the population.

Methods

Two identical cross-sectional studies were performed before (1997–1998, n=4649) and after (2004–2005, n=3570) the initiation of the Danish iodization programme in two areas with mild and moderate iodine deficiency. Serum Tg was measured from blood samples. Thyroid volume was measured by ultrasonography.

Results

Before iodization, the median serum Tg was considerably higher in moderate than in mild iodine deficiency. Iodization led to a lower serum Tg in all examined age groups. The marked pre-iodization difference in Tg level between the regions was eliminated. The prevalence of Tg above the suggested reference limit (40 μg/l) decreased from 11.3 to 3.7% (P<0.0001). Using bootstrapping, we demonstrated a higher efficacy of Tg than of thyroid volume to show a difference between pre- and post-iodization values.

Conclusion

We found serum Tg to be a suitable marker of iodine nutrition status in the population. The results may suggest that the Danish iodization programme has led to a sufficient iodine intake, even if the median UI excretion is still marginally low according to WHO criteria.

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Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case–control study

Allan Carlé, Inge Bülow Pedersen, Nils Knudsen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, Torben Jørgensen, and Peter Laurberg

Objective

Alcohol consumption is an important protective risk factor for many autoimmune diseases. We wished to study the association between alcohol consumption and autoimmune hypothyroidism.

Design

Population-based, case–control study, 1997–2001, Denmark.

Methods

Patients with newly diagnosed autoimmune overt hypothyroidism (n=140) were prospectively identified in a population (2 027 208 person-years of observation), and their matched controls with normal thyroid function (n=560) were recruited simultaneously from the same population. Participants gave information on alcohol intake, smoking, previous diseases, education, and family history of hypothyroidism. The association between alcohol intake and development of hypothyroidism was analyzed in conditional regression models.

Results

Hypothyroid cases had reported a lower alcohol consumption than controls (median units of alcohol (12 g) per week: 3 vs 5, P=0.002). In a multivariate regression model, alcohol consumption was associated with a reduction in risk for development of overt autoimmune hypothyroidism. Odds ratios (95% confidence interval) compared with the reference group with a recent (last year) consumption of 1–10 units of alcohol per week were as follows: 0 units/week, 1.98 (1.21–3.33); 11–20 units/week, 0.41 (0.20–0.83); and ≥21 units/week, 0.90 (0.41–2.00). Similar results were found for maximum previous alcohol consumption during a calendar year. No interaction was found with type of alcohol consumed (wine vs beer), sex, or region of inhabitancy.

Conclusions

Alcohol consumption seems to confer considerable protection against development of overt autoimmune hypothyroidism irrespective of sex and type of alcohol consumed.

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Iodine fortification may influence the age-related change in thyroid volume: a longitudinal population-based study (DanThyr)

Anne Krejbjerg, Lena Bjergved, Inge Bülow Pedersen, Allan Carlé, Torben Jørgensen, Hans Perrild, Lars Ovesen, Lone Banke Rasmussen, Nils Knudsen, and Peter Laurberg

Objective

To assess the individuals' thyroid volume changes after the mandatory nationwide iodine fortification (IF) program in two Danish areas with different iodine intake at baseline (Copenhagen, mild iodine deficiency (ID) and Aalborg, moderate ID).

Design

A longitudinal population-based study (DanThyr).

Methods

We examined 2465 adults before (1997) and after (2008) the Danish IF of salt (2000). Ultrasonography was carried out by the same sonographers using the same equipment, after controlling performances. Participants treated for thyroid disease were excluded from analyses.

Results

Overall, median thyroid volume had increased in Copenhagen (11.8–12.2 ml, P=0.001) and decreased in Aalborg, although not significantly (13.3–13.1 ml, P=0.07) during the 11 years of follow-up.

In both regions, there was an age-related trend in individual changes in thyroid volume from baseline to follow-up; thyroid volume increased in women <40 years of age and decreased in women >40 years of age.

In a multivariate regression model, higher age at entry was a predictor (P<0.05) for thyroid volume decrease >20% during the follow-up period (women aged 40–45 years: odds ratio (OR) 4.3 (95% CI, 2.2–8.2); women aged 60–65 years: 5.8 (2.9–11.6)) and individuals of higher age were also less likely to have an increase in thyroid volume (women aged 40–45 years: OR 0.2 (0.1–0.3); women aged 60–65: OR 0.3 (0.2–0.4)).

Conclusions

Age-dependent differences in thyroid volume and enlargement had leveled out after the Danish iodization program. Thus, the previously observed increase in thyroid volume with age may have been caused by ID.

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The diurnal variation of bone formation is attenuated in adult patients with type 2 diabetes

Katrine Hygum, Jakob Starup-Linde, Torben Harsløf, Niklas Rye Jørgensen, Bolette Hartmann, Jens Juul Holst, and Bente L Langdahl

Objective

Bone turnover has a diurnal variation influenced by food intake, incretin hormones, the sympathetic nervous system and osteocyte function. The aim of the study was to compare diurnal variation in bone turnover in patients with diabetes and controls.

Design

A clinical 24-h study with patients with type 1 diabetes (n = 5), patients with type 2 diabetes (n = 5) and controls (n = 5).

Methods

Inclusion criterion: age >50 years. Exclusion criteria: diseases/medication that affect bone metabolism or recent use of incretin-based drugs. We drew blood samples hourly during the day and every 3 h during the night. We served an identical diet on all study days. We used repeated-measures one-way ANOVA to compare the levels of the investigated markers, and we quantified the effect of time by comparing group mean standard deviations.

Results

The bone formation marker procollagen type 1 N-terminal propeptide showed a significant interaction between time and group (P = 0.01), and the mean standard deviation was lower in patients with type 2 diabetes compared with controls (P = 0.04) and patients with type 1 diabetes (P = 0.02). Other markers of bone formation and resorption showed significant effect of time. Levels of glucagon-like peptide-2, glucose-dependent insulinotropic peptide and sclerostin only showed significant effect of time (all P values 0.01), but levels of sclerostin tended to being highest in type 2 diabetes and lowest in controls.

Conclusions

The diurnal variation in bone formation is attenuated in patients with type 2 diabetes. This is not explained by changes in incretin hormone levels, but possibly mediated by sclerostin.