J. Møller

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.

Dose-response studies on the metabolic effects of a growth hormone pulse in humans☆

Whereas the lipolytic and diabetogenic consequences of sustained growth hormone (GH) exposure are well described, the metabolic effects of a short-lived physiological GH pulse have only recently been reported. To assess the possible dose-response of such short-term bolus administration of GH, six healthy, male subjects were each studied thrice for 4 1/2 hours after an intravenous (IV) bolus of either 70, 140, or 350 micrograms GH, resulting in peak GH concentrations of 10, 15, and 34 micrograms/L. Observed results include: (1) Time- (but not dose-) dependent changes (P less than .05) in plasma glucose and an acute (from 10 minutes onward), persistent, 40% decrease in forearm glucose uptake. Total glucose turnover decreased steadily with time on all occasions. (2) Time- and dose-dependent increases (P less than .05) in the concentrations of circulating lipid intermediates, with an increase of 3-hydroxybutyrate (3-OHB) from a basal of 35 mumol/L to peak values of 108 +/- 34 (70 micrograms), 176 +/- 46 (140 micrograms), and 232 +/- 51 mumol/L (350 micrograms), forearm uptake of 3-OHB changed in parallel. (3) Respiratory exchange ratio decreased (P less than .05) with increasing GH doses (indicating increased lipid and decreased glucose oxidation), and energy expenditure remained unaffected. (4) Concentrations of insulin, C-peptide, and glucagon were unchanged throughout all studies. We conclude that the stimulating effects of a modest GH bolus on circulating lipid intermediates and lipid oxidation are dose-dependent. This finding underlines the potential role of GH as a principal physiological regulator of fuel consumption in the maintenance of metabolic homeostasis.

Metabolic effects of growth hormone in humans

Growth hormone (GH) has acute actions to stimulate lipolysis and ketogenesis after 2 to 3 hours, effects that may be important in the adaptation to stress and fasting. This is accompanied by a decrease in insulin sensitivity in both liver and muscle. These combined effects may be very deleterious to insulin-dependent diabetic patients, in whom increased GH secretion may precipitate and maintain acute metabolic derangement (ketoacidosis) and be a major initiator of the dawn phenomenon. On the other hand, augmented GH secretion plays a beneficial role in the defense against hypoglycemia, in particular during prolonged hypoglycemia and in patients with impaired ability to secrete other counterregulatory hormones appropriately. It is also certain that GH is a potent anabolic hormone in terms of promoted nitrogen retention, but the extent to which these well-known actions are direct or secondary to hyperinsulinemia, increased activity of insulin-like growth factors (IGFs), or release of protein-conserving lipid intermediates has eluded precise characterization.

Adult Growth Hormone Deficiency

Several reports have focused on the clinical features of the untreated GH-deficient adult and the effect of GH therapy. The results reported are strikingly unanimous. Untreated GH-deficient adults have been shown to have increased cardiovascular mortality, reduced exercise capacity, reduced muscle strength, subnormal glomerular filtration rate and renal plasma flow, defective sweat secretion and defective thermoregulation, reduced energy expenditure and basal metabolic rate, abnormal thyroid hormone metabolism, reduced myocardial function and clinical signs of premature atherosclerosis. Body composition has been found abnormal with increased fat mass, decreased lean body mass, decreased muscle fat ratio, visceral obesity, reduced extracellular fluid volume and reduced bone mineral content. Furthermore, two independent groups have reported impaired psychological wellbeing as compared to normal subjects. Apart from the observation on total mortality, all the above-reported abnormalities improve during GH substitution. The only recognisable side effects so far has been fluid retention, which is usually transient and dose-dependent. It is concluded that GH deficiency has distinct clinical consequences all of which can be totally or partially alleviated by GH replacement therapy.

Unicompartmental arthroplasty of the knee Cadaver study of the importance of the anterior cruciate ligament

The tibiofemoral articulation on horizontal and 10 degrees tilted tibial components was examined radiographically in 20 cadaver knees after lateral arthroplasty, and after cutting the anterior cruciate ligament in 10 knees with medial and 10 with lateral arthroplasty. Articulation took place more posteriorly on the horizontal components at any degree of flexion examined; a correlation was found between the operation-induced change in the inclination of the lateral tibial plateau and the point of articulation. Based on the regression equations, the expected point of articulation on an arbitrarily chosen component placement could be calculated for any degree of flexion provided the preoperative inclination was known. Cutting the anterior cruciate ligament caused articulation to move posteriorly on the tibial component at both medial and lateral arthroplasty. We concluded that it was possible to estimate the tilt of the tibial component that was required to avoid marginal articulations when the preoperative slope of the tibial plateau was known. Absence of the anterior cruciate ligament seems to contraindicate unicompartmental arthroplasty.

Impact of 2 weeks high dose growth hormone treatment on basal and insulin stimulated substrate metabolism in humans

OBJECTIVE Short‐term, high dose growth hormone (GH) treatment has been advocated in many catabolic disease states. It is likely that some of the anabolic effects of GH are mediated through activation of lipolysis, but the metabolic impact of therapeutically relevant GH exposure is not known in detail. The present study was accordingly designed to assess the effects of such GH exposure on basal and insulin stimulated intermediary metabolism.

Fibrin sealant in bone transplantation No effects on blood flow and bone formation in dogs

To study bone formation and regional blood flow following the use of fibrin sealant in autologous cancellous bone transplantation, a dog model was developed. In 18 dogs, a standardized defect in both tibiae was filled with an autologous iliac crest graft. On one side, the bone chips were mixed with fibrin sealant while the other side served as control. After 1, 2 and 3 weeks the blood flow of the transplant was calculated and the new bone formed evaluated histomorphometrically. Generally, the highest blood flow rates and most intensive new bone formation were observed at 2 weeks postoperatively. Fibrin sealant did not alter blood flow or new bone formation, but a tendency to diminished new bone formation was found in some grafts. Our study does not support the application of fibrin sealant in ordinary cancellous bone grafting.

Effects of growth hormone on fluid homeostasis. Clinical and experimental aspects

Regulation of body fluid homeostasis appears simple at first sight since daily sodium and water intake equals daily sodium and water output. The mechanisms enabling the body to excrete exactly the ingested and metabolically produced amounts of water and sodium are, however, complex and not completely understood. The factors regulating body fluid homeostasis may grossly be divided into humoral and physical factors. The former comprises among others the renin–angiotensin–aldosterone system (RAAS), arginine vasopressin (AVP), atrial natriuretic factor (ANF), and prostaglandins. The physical factors relate primarily to renal function and factors regulating osmotic pressure. Approximately 60% of body weight is water, which may be subdivided into intracellular volume (ICV) (40%) in which potassium and phosphate are the predominant cation and anion, respectively, and extracellular volume (ECV) (20%) dominated by sodium and chloride. ECV may further be subdivided into interstitial volume(15%) and plasma volume (PV) (5%) [1]. In principle ECV constitutes the internal environment, which is responsible for the transport of ions, nutrients and hormones vital to the cells. This term was introduced by the French physiologist, Claude Bernard, in 1885. The osmotic concentrations of ECV and ICV are equal under steady-state conditions, but any change result in an osmotic gradient and an immediate flux of water along this gradient until equilibrium is restored [2]. Hence a considerable passage of water occurs across the cell membrane, exemplified by the fact that the water content of an erythrocyte is exchanged 100 times per second without any netmovement of water [3]. Water passes mainly the cell membrane through protein channels, which in turn are influenced by osmotic differences generated by facilitated diffusion and active transport across the cell membrane. A normal subject ingests 2100ml water daily and synthesizes additionally 200ml by oxidation. Daily fluid output in a normal subject includes 700ml from the skin and lungs, 200ml from faeces, and sweat and a urinary output of 1400ml [4]. Between 5 and 10% of total body water is exchanged daily in healthy adults [1]. Total body water (TBW) is traditionally estimated by isotopic dilution. ECV and PV may also be estimated using this principle, whereas ICV assessment is calculated indirectly by combining measurements of TBW and ECV. The role of GH in this complex system is not fully established, but several reports suggest that it is important in body fluid regulation. More than 70 years ago anterior pituitary extracts were shown to induce fluid retention in rats [5] and two decades later GH-induced sodium and fluid retention was also demonstrated in man [6–8]. The sodiumand water-retaining effects of GH have subsequently been confirmed in several studies in normal man, in acromegalic patients and in GH-deficient patients [9–15]. Despite methodological heterogeneity most authors seem to agree that body fluid volume is decreased in GH-deficient adults and that GH treatment normalizes body fluid volume in these patients. There is also agreement that GH causes volume expansion, when administered in pharmacological doses to normal subjects and when secreted in excess in active acromegaly. Regarding the underlying mechanisms attention has focused on direct cellular action of GH [14] and a possible GH-induced stimulation of the renin–angiotensin– aldosterone system (RAAS) [8]. More recently other hormonal systems such as ANF [15], the prostaglandins [16], IGF-I [17], and nitric oxide [18] have been suggested to be involved. At present the sodium and fluidretaining effect of GH seems indisputable, whereas the underlying mechanisms appear to be diverse. www.elsevier.com/locate/ghir Growth Hormone & IGF Research 13 (2003) 55–74

GH-Replacement Therapy in Adults

Growth hormone (GH) deficiency in adults, whether GH deficient since childhood or patients rendered GH deficient in adult life, is associated with psychosocial maladjustment, reduced muscle strength and reduced exercise capacity. Body composition is significantly altered with increased fat and decreased muscle volume as compared to healthy subjects. Kidney function is subnormal, and so is sweat secretion. Epidemiological data suggest premature mortality due to cardiovascular disease in hypopituitary patients. Short-term GH treatment trials have shown improved psychosocial performance, normalization of body composition, increased muscle strength, improved exercise capacity, increased cardiac performance and increase in bone mineral mass as well as in serum markers of bone turnover, and normalization of kidney function. Thus GH replacement therapy in GH-deficient adults exhibits potential long-term beneficial effects. A number of important questions has to be addressed before long-term GH replacement therapy in GH-deficient adults can be considered on a routine basis.

Growth Hormone (GH)-Deficiency in Adults: Clinical Features and Effects of GH Substitution

Growth hormone (GH) replacement therapy in growth retarded GH-deficient children has been used with therapeutic success for 35 years /1,2/. Until recently, GH therapy has been discontinued after cessation of longitudinal growth or achievement of a certain target height or simply at a given chronological age of the patient 121. This approach was not physiologically based but rather dictated by the very limited supply of pituitary derived GH. It had been recognised, even before the availability of reliable GH assays, that GH secretion continues in adulthood, and that experimental administration of GH in adults had distinct metabolic effects. Indeed, Raben was the first to present a favorable response to GH treatment in an adult patient with panhypopituitarism /3/. The introduction of biosynthetic human GH radically changed the clinical conditions, which incidentally coincided with the first alarming reports of a possible association between the use of pituitary GH and contraction of Creutzfeld Jacobs disease