Torben Laursen

Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose‐dependent manner and suppresses circadian thyrotrophin levels: studies in GH‐deficient adults

OBJECTIVE The impact of exogenous GH on thyroid function remains controversial although most data add support to a stimulation of peripheral T4 to T3 conversion. For further elucidation we evaluated iodothyronine and circadian TSH levels in GH‐deficient patients as part of a GH dose‐response study.

Morbidity and GH deficiency: a nationwide study.

OBJECTIVE To estimate morbidity in Denmark in all patients with GH deficiency (GHD). DESIGN Morbidity was analyzed in 1794 GHD patients and 8014 controls matched on age and gender. All records in the GHD patients were studied and additional morbidity noted. Diagnoses and dates of admissions were identified in the National Patient Registry. Lag time until first admission was used as a measure of morbidity. Patients were divided into childhood onset (CO) and adult onset (AO), discriminated by an age cut-off of 18 years at onset of GHD. METHOD Sex- and cause-specific hazard ratios (HRs) in CO and AO GHD compared with controls. RESULTS Total morbidity was significantly increased in the GHD patients. HR for CO males: 3.1 (95% confidence interval (CI): 2.7-3.7), CO females: 3.2 (95% CI: 2.6-3.9), AO males: 2.9 (95% CI: 2.6-3.2), and AO females: 3.2 (95% CI: 2.8-3.6). In 18 out of 20 chapters from the International Classification of Diseases-10, a significantly increased morbidity was identified for at least one of the four subgroups of patients. Morbidity was significantly increased in all the four subgroups due to infectious, endocrine, pulmonary, urogenital, and neurological diseases; cancer; diseases of the eye, ear, and circulatory diseases; and traumas. Fractures were significantly increased in AO females, not in males. CONCLUSIONS Morbidity was significantly increased in the GHD patients. The increased morbidity was due to a variety of disorders, some of which can readily be explained by GHD and other pituitary deficiencies, while others cannot be easily explained.

Metabolic effects of growth hormone administered subcutaneously once or twice daily to growth hormone deficient adults

OBJECTIVE The aim of this study was to compare the metabolic effects of GH administered subcutaneously either once or twice daily. The actions of GH might depend upon a pulsatlle pattern of serum GH. Pulsatile and continuous intravenous delivery of GH, however, induce similar short‐term metabolic effects in GH deficient patients. An improved growth response is obtained in GH deficient children when a fixed weekly GH dose Is administered by dally subcutaneous injections instead of twice or thrice‐weekly intramuscular injections. A more pulsatile pattern and serum GH levels above zero might be achieved by further increasing the Injection frequency. Increased daytime GH levels might, however, adversely affect the circadian patterns of metabolic indices, whlch have been demonstrated to be more successfully reproduced by evening compared with morning GH administration.

Body fluids, circadian blood pressure and plasma renin during growth hormone administration: a placebo-controlled study with two growth hormone doses in healthy adults

Side effects that can be related to fluid retention are common during the initial phases of growth hormone (GH) administration. The aim of this study was to examine the changes in body fluid compartments, diurnal blood pressure and plasma renin concentration during GH administration with two different dosages in healthy adults. Eight healthy male subjects aged 24-32 years were examined during three 2-week study periods in a double-blind placebo controlled study. They received, in random order, GH (3 or 6 IU m-2 daily) or placebo during 2 weeks. Bio-impedance was measured every 2nd day, and extracellular volume (ECV) and plasma volume (PV) were isotopically determined at day 6. Blood samples were obtained regularly. Diurnal blood pressure was recorded and 24-h urinary samples were collected at days 0, 6 and 14. ECV (l) was increased by GH (placebo, 19.58 +/- 0.82; 3 IU m-2, 20.77 +/- 1.22; 6 IU m-2, 20.65 +/- 0.94; p<0.01), whereas PV (l) was unaffected (placebo, 3.91+/- 0.20; 3 IU m-2, 4.04 +/- 0.22; 6 IU m-2, 3.90 +/- 0.27). Total body water (l) increased significantly during GH administration (placebo, 50.8 +/- 2.6; 3 IU m-2, 52.6 +/- 2.3; 6 IU m-2, 53.9 +/- 1.8, p<0.05). After 6 days of treatment a significant increase in renin (p = 0.03) was observed. Mean diurnal blood pressure levels remained unchanged, whereas mean diurnal heart rate (min-1) increased significantly (placebo, 75 +/- 3.6; 3 IU m-2, 79 +/- 3.2; 6 IU m-2, 79 +/- 3.7; p<0.01). In conclusion, GH administration induces an elevation in total body water which may involve a stimulation of plasma renin and an increased ECV without any changes in PV or diurnal blood pressure.

Liquid Growth Hormone: Preservatives and Buffers

Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropin® SimpleXx®, has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3–9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3–4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin® SimpleXx® showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance.

Pegylated Long-Acting Human Growth Hormone Possesses a Promising Once-Weekly Treatment Profile, and Multiple Dosing Is Well Tolerated in Adult Patients with Growth Hormone Deficiency

BACKGROUND Recombinant human GH (rhGH) replacement therapy in children and adults currently requires daily sc injections for several years or lifelong, which may be both inconvenient and distressing for patients. NNC126-0083 is a pegylated rhGH developed for once-weekly administration. OBJECTIVES Our objective was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of NNC126-0083 in adult patients with GH deficiency (GHD). SUBJECTS AND METHODS Thirty-three adult patients with GHD, age 20-65 yr, body mass index 18.5-35.0 kg/m(2), and glycated hemoglobin of 8.0% or below. Fourteen days before randomization, subjects discontinued daily rhGH. NNC126-0083 (0.01, 0.02, 0.04, and 0.08 mg/kg) was given sc once weekly for 3 wk (NNC126-0083 for six subjects and placebo for two subjects). Blood samples were collected up to 168 h after the first and up to 240 h after the third dosing. Physical examination, antibodies, and local tolerability were assessed. RESULTS NNC126-0083 was well tolerated with no difference in local tolerability compared with placebo and with no signs of lipoatrophy. A more than dose-proportional exposure was observed at the highest NNC126-0083 dose (0.16 mg protein/kg). Steady-state pharmacokinetics seemed achieved after the second dosing. A clear dose-dependent pharmacodynamic response in circulating IGF-I levels was observed [from a predose mean (SD) IGF-I SD score of -3.2 (1.7) to peak plasma concentration of -0.5 (1.3), 1.6 (1.3), 2.1 (0.5), and 4.4 (0.9) in the four dose groups, respectively]. CONCLUSION After multiple dosing of NNC126-0083, a sustained pharmacodynamic response was observed. NNC126-0083 has the potential to serve as an efficacious, safe, and well-tolerated once-weekly treatment of adult patients with GHD.

The benefits of growth hormone therapy in patients with Turner syndrome, Noonan syndrome and children born small for gestational age

This review will summarize the effects of growth hormone (GH) on height, body composition, bone and psychosocial parameters in children with Turner syndrome or Noonan syndrome and those born small for gestational age. The safety of GH treatment in children with these diagnoses is also reported. Despite the reported efficacy and safety of GH in these indications, however, not all children achieve their target height potential, due in some part to poor adherence to GH therapy regimens; indeed up to 50% of children are less than fully compliant with treatment. With this in mind the present and future administration of GH therapy is discussed with respect to advances being made in the presentation of GH for injection and advances in GH injection devices. It is hoped that such progress, aimed at making the administration of GH easier and less painful for the patient will improve treatment adherence and outcome benefits.

Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in Type 2 diabetes.

Aims  To compare insulin and glucose profiles during basal continuous subcutaneous infusion of a rapid‐acting insulin analogue and once daily subcutaneous injection of a long‐acting insulin analogue in Type 2 diabetes.

DIFFERENT EFFECTS OF CONTINUOUS AND INTERMITTENT PATTERNS OF GROWTH HORMONE ADMINISTRATION ON LIPOPROTEIN LEVELS IN GROWTH HORMONE-DEFICIENT PATIENTS

Background: Lipoprotein (a) (Lp(a)) is a risk marker for the development of atherosclerotic coronary heart disease. Growth hormone (GH) administration to GH-deficient (GHD) adults increases serum Lp(a) concentrations, and the levels of Lp(a) and GH are correlated in patients with acromegaly. Studies in rats have demonstrated differential effects of constant and intermittent GH patterns on levels of certain lipoproteins. The aim of the present studies was to describe the impact of intermittent and continuous patterns of GH delivery to GHD patients on serum levels of Lp(a) and other lipoproteins. Methods: In one study (A) 10 GHD patients received in random order a fixed GH dose intravenously as: (1) continuous infusion; (2) eight bolus injections, and (3) a combination of 1 and 2. Each study lasted 36 h and was preceded by at least 4 weeks without GH. In another study (B) 13 GHD patients received GH in random order as: (1) continuous subcutaneous (s.c.) infusion, and (2) daily s.c. injections in the evening for 1 month each. The patients were studied during steady-state conditions at the end of each treatment period. Results: In study A Lp(a) levels increased significantly following continuous (p < 0.05) and combined patterns (p < 0.02) of GH administration to GH-deprived GHD patients, whereas the increase after GH bolus injections alone was not significant (p = 0.14). In study B significantly higher (p < 0.05) serum levels of Lp(a) were obtained after continuous s.c. infusion as compared with daily s.c. injections of GH. Concentrations of the high-density lipoprotein (HDL) cholesterol were significantly lower (p < 0.02) after the continuous GH pattern. Similarly, the HDL fraction Apo A-1 tended to be lower with constant GH delivery (p = 0.052). Serum levels of total cholesterol, triglyceride and Apo B were similar on the two occasions. Conclusion: Short-term GH administration to GH-deprived GHD patients increased serum Lp(a), but only significantly with continuous delivery. During more prolonged GH exposure, constant s.c. infusion of GH resulted in slightly raised Lp(a) levels and reduced HDL and Apo A1 levels as compared with intermittently administered GH. The findings are consistent with the more effective induction of serum IGF-I levels after continuous patterns of GH delivery previously reported in GHD patients. Longer-term data are needed before conclusions with respect to the impact of the pattern of GH administration on, e.g., the risk of developing coronary heart disease can be drawn.

Pharmacokinetics and metabolic effects of growth hormone injected subcutaneously in growth hormone deficient patients: thigh versus abdomen.

OBJECTIVE The absorption of insulin following subcutaneous (s.c.) injection is faster in the abdomen than the thigh. We therefore studied the effect of changing the site of injection on the absorption and metabolic effects of human growth hormone.