Growth hormone and bone.

It is well known that GH is important in the regulation of longitudinal bone growth. Its role in the regulation of bone metabolism in man has not been understood until recently. Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and bone resorption. In Figure 9 a simplified model for the cellular effects of GH in the regulation of bone remodeling is presented (Fig. 9). GH increases bone formation in two ways: via a direct interaction with GHRs on osteoblasts and via an induction of endocrine and autocrine/paracrine IGF-I. It is difficult to say how much of the GH effect is mediated by IGFs and how much is IGF-independent. GH treatment also results in increased bone resorption. It is still unknown whether osteoclasts express functional GHRs, but recent in vitro studies indicate that GH regulates osteoclast formation in bone marrow cultures. Possible modulations of the GH/IGF axis by glucocorticoids and estrogens are also included in Fig. 9. GH deficiency results in a decreased bone mass in both man and experimental animals. Long-term treatment (> 18 months) of GHD patients with GH results in an increased bone mass. GH treatment also increases bone mass and the total mechanical strength of bones in rats with a normal GH secretion. Recent clinical studies demonstrate that GH treatment of patients with normal GH secretion increases biochemical markers for both bone formation and bone resorption. Because of the short duration of GH treatment in man with normal GH secretion, the effect on bone mass is still inconclusive. Interestingly, GH treatment to GHD adults initially results in increased bone resorption with an increased number of bone-remodeling units and more newly produced unmineralized bone, resulting in an apparent low or unchanged bone mass. However, GH treatment for more than 18 months gives increased bone formation and bone mineralization of newly produced bone and a concomitant increase in bone mass as determined with DEXA. Thus, the action of GH on bone metabolism in GHD adults is 2-fold: it stimulates both bone resorption and bone formation. We therefore propose "the biphasic model" of GH action in bone remodeling (Fig. 10). According to this model, GH initially increases bone resorption with a concomitant bone loss that is followed by a phase of increased bone formation. After the moment when bone formation is stimulated more than bone resorption (transition point), bone mass is increased. However, a net gain of bone mass caused by GH may take some time as the initial decrease in bone mass must first be replaced (Fig. 10). When all clinical studies of GH treatment of GHD adults are taken into account, it appears that the "transition point" occurs after approximately 6 months and that a net increase of bone mass will be seen after 12-18 months of GH treatment. It should be emphasized that the biphasic model of GH action in bone remodeling is based on findings in GHD adults. It remains to be clarified whether or not it is valid for subjects with normal GH secretion. A treatment intended to increase the effects of GH/IGF-I axis on bone metabolism might include: 1) GH, 2) IGF, 3) other hormones/factors increasing the local IGF-I production in bone, and 4) GH-releasing factors. Other hormones/growth factors increasing local IGF may be important but are not discussed in this article. IGF-I has been shown to increase bone mass in animal models and biochemical markers in humans. However, no effect on bone mass has yet been presented in humans. Because the financial cost for GH treatment is high it has been suggested that GH-releasing factors might be used to stimulate the GH/IGF-I axis. The advantage of GH-releasing factors over GH is that some of them can be administered orally and that they may induce a more physiological GH secretion. (ABSTRACT TRUNCATED)

A 10-year, prospective study of the metabolic effects of growth hormone replacement in adults.

CONTEXT: Only a few studies have investigated the effects of GH replacement in adults for more than 5 yr. OBJECTIVE/DESIGN/PATIENTS: In a prospective, open-label, single-center study, the effects of 10-yr GH replacement were determined. Eighty-seven consecutive patients (52 men and 35 women), with a mean age of 44.1 (range 22-74) yr with adult-onset GH deficiency (GHD) were included. RESULTS: The initial mean dose of GH (0.98 mg/d) was reduced during the study and at yr 10 was 0.47 mg/d. The mean IGF-I sd score increased from -1.81 at baseline to 1.29 at study end. The absolute reduction in total body fat was transient. However, after correction for age and sex using a four-compartment model, the reduction in body fat was sustained during the 10-yr study period. There was a sustained improvement in serum lipid profile and after 10 yr, and blood glycosylated hemoglobin level was reduced. The treatment responses in IGF-I sd score, serum high-density lipoprotein cholesterol level, and body composition as measured using dual-energy x-ray absorptiometry were more marked in men, whereas women had a more marked reduction in blood glycosylated hemoglobin level. CONCLUSION: The effect on the absolute amount of body fat was seen early and was transient, which could be due to the normal aging of the patients. The effects on metabolic indices were detected later, but they were sustained and even progressive throughout the study period.

Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency.

UNLABELLED: There are few studies that have determined the effects of long-term GH replacement on bone mineral density (BMD) in GH-deficient (GHD) adults. In this study, the effects of 10 years of GH replacement on BMD were assessed in 87 GHD adults using dual energy X-ray absorptiometry (DEXA). The results show that GH replacement induced a sustained increase in BMD at all the skeletal sites measured. INTRODUCTION: Little is known of the effect of more than 5 years of GH replacement therapy on bone metabolism in GHD adults. PATIENTS AND METHODS: In this prospective, open-label, single-center study, which included 87 consecutive adults (52 men and 35 women; mean age of 44.1 (range 22-74) years) with adulthood onset GHD, the effect of 10 years of GH replacement on BMD was determined. RESULTS: The mean initial dose of GH was 0.98 mg/day. The dose was gradually lowered and after 10 years the mean dose was 0.47 mg/day. The mean insulin-like growth factor-I (IGF-I) SDS increased from 1.81 at baseline to 1.29 at study end. The GH replacement induced a sustained increase in total, lumbar (L2-L4) and femur neck BMD, and bone mineral content (BMC) as measured by DEXA. The treatment response in IGF-I SDS was more marked in men, whereas women had a more marked increase in the total body BMC and the total body z-score. There was a tendency for women on estrogen treatment to have a larger increase in bone mass and density compared with women without estrogen replacement. CONCLUSIONS: Ten years of GH replacement in hypopituitary adults induced a sustained, and in some variables even a progressive, increase in bone mass and bone density. The study results also suggest that adequate estrogen replacement is needed in order to have an optimal response in BMD in GHD women.

Detection of growth hormone abuse in sport.

OBJECTIVE: To develop a test for GH abuse in sport. DESIGN: A double blind placebo controlled study of one month's GH administration to 102 healthy non-competing but trained subjects. Blood levels of nine markers of GH action were measured throughout the study and for 56 days after cessation of GH administration. Blood samples were also taken from 813 elite athletes both in and out of competition. RESULTS: GH caused a significant change in the nine measured blood markers. Men were more sensitive to the effects of GH than women. IGF-I and N-terminal extension peptide of procollagen type III were selected to construct formulae which gave optimal discrimination between the GH and placebo groups. Adjustments were made to account for the fall in IGF-I and P-III-P with age and the altered distribution seen in elite athletes. Using a cut-off specificity of 1:10,000 these formulae would allow the detection of up to 86% of men and 60% of women abusing GH at the doses used in this study. CONCLUSIONS: We report a methodology that will allow the detection of GH abuse. This will provide the basis of a robust and enforceable test identifying those who are already cheating and provide a deterrent to those who may be tempted to do so.

The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. .

To assess the influence of factors affecting fracture risk and bone density in adult hypopituitary patients with growth hormone deficiency (GHD), data from a large-scale pharmacoepidemiological survey (the Pharmacia & Upjohn International Metabolic Database [KIMS]) were analyzed and compared with data from a control population (the European Vertebral Osteoporosis Study [EVOS]). The KIMS group consisted of 2084 patients (1112 men and 972 women) with various types of pituitary disease and EVOS consisted of 1176 individuals (581 men and 595 women). Fracture and bone mineral density (BMD) data were available from 2024 patients from the KIMS group and 392 patients from EVOS. The prevalence of fractures in patients with hypopituitarism was 2.66 times that in the non-GH-deficient EVOS population. Adult-onset hypopituitarism with GHD was associated with a higher fracture risk than childhood-onset disease, and patients with isolated GHD had a similar prevalence of fractures to those with multiple pituitary hormone deficiencies. Hormonal replacement therapy with L-thyroxine, glucocorticoids, and sex steroids did not affect the risk of fracture in KIMS patients. In addition, fracture rates in KIMS were independent of body mass index (BMI) and the country of origin. However, smoking was associated with a higher fracture rate in this group. In summary, this is the first large-scale analysis to support the hypothesis of an increased fracture risk in adult patients with hypopituitarism and GHD. This increased risk appears to be attributable to GHD alone, rather than to other pituitary hormone deficiencies or to their replacement therapy.

Treatment with the oral growth hormone secretagogue MK-677 increases markers of bone formation and bone resorption in obese young males.

The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK-677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double-blind, parallel, placebo-controlled study. Twenty-four healthy obese males, 19-49 years of age, with body mass index > 30 kg/m2 were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK-677 increased markers of bone formation; a 23% increase in the carboxy-terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK-677 treatment (p < 0.01 and p = 0.001 vs. placebo, respectively) while a 15% increase in serum levels of osteocalcin was not detected until 8 weeks of treatment (p < 0.01 vs. placebo). Markers of bone resorption were induced within 2 weeks of treatment with MK-677; serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen were increased 26% at 8 weeks (p = 0.001 vs. placebo), and urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% (p < 0.05 vs. placebo) and 46% (p < 0.05 vs placebo), respectively, MK-677 increased serum insulin-like growth factor binding protein-5 (IGFBP-5) by 43-44% after 2-8 weeks of treatment (p < 0.01 vs. placebo). Serum IGFBP-4 was increased by 25% after 2 weeks of treatment (p < 0.001 vs. placebo) but no significant change from baseline was observed after 8 weeks of treatment. Plasma interleukin-6 was not significantly changed by active treatment. In conclusion, short-term treatment of healthy obese male volunteers with the GH secretagogue MK-677 increases markers of both bone resorption and formation. Large increases in serum levels of IGF-1 and IGFBP-5 and a transient increase in serum IGFBP-4 were found. Future long-term studies are needed to investigate if prolonged treatment with MK-677 increases bone mass.

The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction.

Several studies have shown that GH can enhance cardiac performance in rats after experimental myocardial infarction and in humans with congestive heart failure. In the present study, the hemodynamic effects of hexarelin (Hex), an analog of GH-releasing peptide-6 and a potent GH secretagogue, were compared with the effects of GH. Four weeks after ligation of the left coronary artery male rats were treated sc twice daily with hexarelin [10 microg/kg x day (Hex10) or 100 microg/kg x day (Hex100)], recombinant human GH (2.5 mg/kg x day), or 0.9% NaCl for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. GH, but not Hex, increased body weight gain. GH and Hex100 decreased total peripheral resistance (P < 0.05) and increased stroke volume (P < 0.05 and P < 0.01, respectively) and stroke volume index (P = 0.06 and P < 0.01, respectively) vs. NaCl. Cardiac output was increased by GH and Hex100 (P < 0.05), and cardiac index was increased by Hex100 with a borderline significance for GH (P = 0.06). In conclusion, Hex improves cardiac function and decreases peripheral resistance to a similar extent as exogenous GH in rats postmyocardial infarction. The mechanisms of these effects are unclear; they could be mediated by GH or a direct effect of Hex on the cardiovascular system.

Discontinuation of growth hormone (GH) treatment: metabolic effects in GH-deficient and GH-sufficient adolescent patients compared with control subjects. Swedish Study Group for Growth Hormone Treatment in Children.

The need for continuing GH replacement in patients with childhood-onset GH deficiency continuing into adulthood has been recognized. The metabolic consequences of discontinuing GH in adolescent patients with childhood-onset GH deficiency and short stature were examined over a period of 2 yr. Forty adolescents (aged 16-21 yr) receiving GH treatment for more than 3 yr and 16 closely matched healthy controls were studied. After a baseline visit, GH treatment was discontinued. The patients were then examined with the same protocol once a year for 2 yr. Twenty-one patients had severe GH deficiency (GHD) into adulthood, whereas 19 patients were regarded as having sufficient endogenous GH secretion (GHS). After 2 yr without GH treatment, the serum insulin-like growth factor I level was lower in GHD than in both GHS and control subjects. Both before and 2 yr after GH treatment was discontinued, serum concentrations of total cholesterol (C), low density lipoprotein C, and apolipoprotein B were higher in the GHD than in both GHS and control subjects. Serum concentrations of high density lipoprotein C decreased in the GHD group and increased in the other 2 study groups. The amount of total body and abdominal fat mass throughout the study and the increment in these masses were more marked in the GHD than in the GHS and control subjects when GH treatment was discontinued. The discontinuation of GH therapy in adolescents with severe GHD continuing into adulthood results over a period of 2 yr in the accumulation of important cardiovascular risk factors that are associated with GHD in adults.

Two years of growth hormone (GH) treatment increase isometric and isokinetic muscle strength in GH-deficient adults.

GH deficiency in adults is associated with reduced muscle mass and muscle strength. The objective of this trial was to follow the effect of 2 yr of GH treatment in GH-deficient adults on muscle performance in relation to a reference population. Knee extensor and flexor strengths for isometric and isokinetic concentric muscle strength were measured using a Kin-Com dynamometer. Hand-grip strength was measured in both hands. The fatigue index was calculated as the percent reduction in peak torque at 50 repeated isokinetic knee extensions. Superimposed, single twitch electrical stimulation was performed. The GH-deficient subjects had lower isometric knee extensor, knee flexor, and hand-grip strength than the reference population. Two years of GH treatment increased and normalized the mean isometric knee extensor and flexor strengths. The concentric knee flexor and extensor strength at an angular velocity of pi rad/s increased, as did the concentric knee flexor strength at an angular velocity of pi/3 rad/s. The increase in muscle strength was more marked in younger patients and in patients with lower initial muscle strength than predicted. Quadriceps endurance decreased, whereas the effect of superimposing single twitches on isometric contraction and hand-grip strength was unaffected by the GH treatment. Two years of GH therapy in GH-deficient adults increased and normalized isokinetic and isometric muscle strength studied in proximal muscle groups. Hand-grip strength and the degree of lack of maximal motor unit activation on voluntary isometric knee extensor force did not change. The dynamic local muscle fatigue index decreased.

Pituitary adenomas in Sweden between 1958 and 1991: incidence, survival, and mortality.

The objective of the present study was to determine the incidence of pituitary adenomas (PAs) and the associated rates and causes of mortality in a large population. The study population comprised 2279 patients (1010 women and 1269 men) of all individuals (n = 3321) with pituitary tumors included in the Swedish Cancer Registry between 1958 and 1991. The mean age (+/-SD) at diagnosis was 52.3 +/-15.7 yr. The age-standardized incidence of PA increased significantly from approximately 6 cases/million inhabitants in 1958 to 11 cases/ million in 1991. The age-specific incidence peaked between 60-70 yr of age in both sexes. Excess mortality was found in the study population. The total number of deaths was 842. The standardized mortality ratio (SMR) for the study population was 2.0. The SMR for women (2.3) was significantly (P < 0.01) higher than that for men (1.9). Cardiovascular diseases were the most common cause of mortality among patients, accounting for 346 deaths (SMR, 1.6). The difference between the sexes was significant (men, 1.4; women, 1.8; P < 0.05). Cerebrovascular death occurred in 97 patients (SMR, 2.4), with no significant difference between men (SMR, 2.5) and women (SMR, 2.2). Excess mortality was also observed for tumors, endocrine diseases, and gastrointestinal diseases. These findings suggest that the annual incidence of PA is increasing. Possible explanations are improved diagnostic skill and/or increased awareness of pituitary diseases among physicians. However, a real increase in the incidence of PA cannot be ruled out.

Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy.

A retrospective comparison was performed between 1411 hypopituitary adults without GH replacement [mean age, 56.9 (sd 18.6) yr] and the normal population in terms of fatal and nonfatal morbidity. A similar prospective comparison was then made in 289 hypopituitary patients on long-term GH replacement [mean age, 47.6 (sd 14.8) yr; mean duration of GH treatment, 60 months]. In the 1411 hypopituitary patients without GH replacement, overall mortality (P < 0.001), and the rates of myocardial infarctions (P < 0.01), cerebrovascular events (P < 0.001), and malignancies (P < 0.001) were increased compared with the normal population. Colorectal cancer was the most common malignancy in this cohort (P < 0.001 vs. the background population). In the 289 hypopituitary patients on GH replacement, overall mortality and the rate of malignancies were similar to the normal population. In the hypopituitary adults on GH therapy, the rate of myocardial infarctions was lower than that in the background population (P < 0.05), and there was a tendency toward an increased rate of cerebrovascular events. In conclusion, overall mortality and the rate of myocardial infarctions were increased in hypopituitary patients without GH replacement. An increased rate of malignancies was observed in the hypopituitary adults without GH therapy, with a predominance of colorectal cancer. GH replacement appeared to provide protection from myocardial infarctions. The rate of cerebrovascular events tended to be increased also in hypopituitary adults on GH therapy.

Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency.

The main purpose of this trial was to determine the effects of 2 yr of GH treatment on bone mineral density (BMD) and bone metabolism in patients with adult-onset GH deficiency. Forty-four patients (24 men and 20 women; aged 23-66 yr) participated in a 2-yr open treatment trial with recombinant human GH. BMD was assessed with dual energy x-ray absorptiometry, and serum concentrations of osteocalcin, carboxy-terminal propeptide of type I procollagen (PICP), and carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) were measured. After 2 yr of GH treatment, the BMD increased in the lumbar spine L2-L4 by 3.8% [95% confidence interval (CI), 2.1-5.5], in the femoral neck by 4.1% (CI, 2.1-6.1) in the femoral trochanter by 5.6% (CI, 3.8-7.4) and in Ward's triangle by 4.9% (CI, 2.2-7.6) compared with baseline. Patients with a z-score (difference in SD from the mean of age- and sex-matched subjects) below -1 SD responded with the most marked BMD increment. The serum concentrations of osteocalcin, PICP, and ICTP remained higher throughout the 2 yr of treatment. Women demonstrated a more marked increase in total body BMD and a less pronounced initial increment in osteocalcin, PICP, and ICTP than men. Two years of GH treatment induced a sustained increase in overall bone remodeling activity, which resulted in a net gain in BMD that was more marked in those subjects with a low pretreatment z-score.

GH is needed for the maturation of muscle mass and strength in adolescents.

The postpubertal period and the early years of adulthood may be of importance for continuing tissue maturation of importance in adulthood and aging. An example of this is the peak bone mass. This study has evaluated the importance of GH for lean mass and muscle strength in adolescents and young adults. GH treatment was discontinued in 40 adolescents aged 16-21 yr with GH deficiency of childhood onset. Measurements of isometric and isokinetic knee-extensor and flexor strength, handgrip strength, lean body mass, fat-free mass, and total body nitrogen were performed annually for 2 yr. Two hundred fifty healthy adolescents were randomly selected for prospective measurements of lean mass and handgrip strength between the ages of 17 and 21 yr. In the adolescents with continuing GH deficiency, lean body mass decreased, compared with the patients defined as having sufficient endogenous GH. The isometric strength in knee flexors increased in the sufficient endogenous GH group and was unchanged in the GH deficiency group during the 2 yr off GH treatment (between group, P < 0.05). The mean and peak handgrip strength increased on average by 9-15% in the group with sufficient endogenous GH and was unchanged in those with GH deficiency (P < 0.05). Lean body mass and handgrip strength (both, P < 0.001) increased in both the healthy boys and girls who were followed for 4 yr with a more marked increase in the boys. The mean increase in handgrip between the age of 17 and 21 yr was 7-9%. The increased lean mass and improved muscle performance seen in healthy adolescents did not occur in adolescents with GH deficiency. These findings suggest that GH is of importance for the maturation of lean mass and muscle strength in adolescents and young adults.

Circulating non-22-kilodalton growth hormone isoforms in acromegalic men before and after transsphenoidal surgery.

GH represents several molecular isoforms in addition to the main 22-kDa (22K) GH. There have been reports suggesting that circulating non-22K GH isoforms are increased in acromegaly, but the possible implications of such observations in the management of the disease have not been addressed. The aim of this study was to evaluate the proportion of circulating non-22K GH isoforms in acromegaly. In addition, the relationships between the amount of non-22K GH and tumor size, biochemical measurements, and body composition also were investigated. Samples with different GH levels were selected from 24-h GH profiles from 15 acromegalic men evaluated before and 1 yr after transsphenoidal surgery and from 13 healthy men. The serum non-22K GH levels, expressed as percentage of total GH concentration, were determined by the 22K GH exclusion assay, which is based on immunomagnetic extraction of 22K GH from serum and quantitation of non-22K GH using a polyclonal GH assay. The proportion of non-22K GH isoforms was fairly constant in different samples from the same patient, regardless of the GH level. However, a wide variation of values was observed among acromegalics, both before (14-51%) and after surgery (8-62%). The proportion of non-22K GH isoforms was increased in untreated patients, compared with controls (26.6 vs. 17.4%; P < 0.01), and the values correlated significantly to tumor size, mean 24-h GH concentration, serum PRL, and extracellular water. After surgery, patients not truly cured, with mean 24-h GH concentration of 1 microg/L or more, had an increased proportion of non-22K GH, compared with those with levels less than 1 microg/L (P < 0.01). In the former group, the median values were similar than those in untreated acromegalics (34 vs. 26.6%, respectively), whereas in the latter, they were comparable with those in the controls (15.2 vs. 17.4%, respectively). We conclude that acromegalics have an increased proportion of circulating non-22K GH isoforms. The values are fairly constant in different samples from an individual, regardless of GH level, but a large spectrum can be observed among patients. This variability suggests that different pituitary adenomas secrete GH isoforms in variable amounts. Our observation that a higher proportion of non-22K GH isoforms is present in patients not truly cured after surgery suggests that the evaluation of non-22K GH isoforms can be useful in the follow-up of acromegalic patients.

Diurnal variations in twenty-four-hour energy expenditure during growth hormone treatment of adults with pituitary deficiency.

The effects of growth hormone (GH) treatment on 24-h energy expenditure (EE) were studied in a open trial over a period of 4 weeks. Five subjects, four men and one woman, with a history of complete GH deficiency were included. All the subjects were examined on 2 consecutive days on baseline and, thereafter, at six occasions during a period of 1 month (days 1, 2, 5, 8, 15, and 30). The dose of GH was 0.25 U/kg.week, administered sc once a day in the evening. EE was determined in a chamber for indirect calorimetry. Body composition was determined with dual-energy x-ray absorptiometry and computed tomography using a four-scan technique. Blood samples were examined using well-established RIAs. During the first 2 weeks, 24-h EE increased by 6 +/- 3% (range 1-8%) from 40.9 +/- 4.8 to 42.9 +/- 4.8 kcal/24 h.kg (P < 0.05), sleeping metabolic rate by 14 +/- 3% (range 10-18%) from 28.4 +/- 1.9 to 32.9 +/- 2.2 kcal/24h.kg (P < 0.001), and basal metabolic rate by 11 +/- 7% (range 0-18%) from 29.6 +/- 2.4 to 33.3 +/- 2.6 kcal/24h.kg (P < 0.05). No change was found in daytime EE. The increase in EE covaried with changes in insulin-like growth factor 1, the free T3/free T4 ratio, insulin-like growth factor-binding protein-3, and the aminoterminal procollagen III peptide but not with changes in body composition. It is suggested that the stimulating effect of GH on EE occurs gradually during a 2-week period and is only detectable during night and morning hours, when significant levels of GH occur.

Assimilation of triglycerides in subcutaneous and intraabdominal adipose tissues in vivo in men: effects of testosterone.

To determine the effects of testosterone (T) on lipid assimilation in different adipose tissue depots, T (250 mg, im) was given to 17 middle-aged men 5 days before abdominal surgery. Twenty-four hours before surgery, 10 microCi labeled oleic acid in 80 g milk fat were administered orally. Lipid radioactivity was measured in adipose tissue biopsies from abdominal ac, omental, and retroperitoneal adipose tissues. Subcutaneous, visceral (omental plus mesenteric), and retroperitoneal adipose tissue masses were determined using computerized tomography scans at 22 levels. Sixteen men who were not treated with T served as controls. T administration was followed by an increase in serum concentrations from 17.7 +/- 1.1 to 32.6 +/- 1.8 nmol/L (P < 0.001) and a marked (> 50%) reduction compared with controls in lipid radioactivity in omental and retroperitoneal adipose tissues, but not in sc adipose tissue. In controls, sc, visceral, and retroperitoneal adipose tissues assimilated 59.2 g (73.4%), 16.9 g (20.9%), and 4.6 g (5.7%), respectively, of the orally administered fat. In the T-treated men, this was changed to 73.5 g (88.8%), 6.4 g (7.7%), and 2.9 g (3.5%), respectively. It was concluded that T inhibits triglyceride assimilation in intra-abdominal depots and apparently directs this lipid to sc fat in men.

Treatment of growth hormone deficiency in adults.

In analogy with other hormonal replacement therapy GH treatment should be commenced with a low starting dose, independent of body weight or body surface area. Hormonal replacement should mimic the normal physiology to minimize the risk of side effects in the life-long replacement of adults. We should, therefore, consider individual responsiveness and also be aware of the difference between pattern of GH under normal condition and during s.c. administration. The safety and monitoring of GH replacement therapy in adults have been addressed in the Growth Hormone Research Society Consensus Guidelines for Diagnosis and Treatment of Adults with GH Deficiency from the Port Stephens Workshop, April 1997. Besides finding better and more accurate biochemical markers for choosing correct GH replacement dose, future research should address the long-term benefits and safety with GH replacement in adults, with special emphasize on incipient risks in terms of cardiovascular disease and of neoplasia, in particular.

Intense sympathetic nerve activity in adults with hypopituitarism and untreated growth hormone deficiency.

Perturbations in the sympathetic nervous system may be anticipated in adults with hypopituitarism and untreated GH deficiency, because the syndrome is associated with both peripheral and central factors known to modulate sympathetic traffic. The higher prevalence of hypertension and increased cardiovascular morbidity/mortality reported in GH-deficient patients may suggest increased activity of the sympathetic nervous system. We recorded muscle sympathetic nerve activity (MSNA) in 10 hypopituitary adults with adequate hormonal replacement therapy except GH and in 10 healthy controls matched for age, gender, and body mass index to test whether hormonal aberrations in hypopituitarism and untreated GH deficiency are associated with an increase in sympathetic nerve traffic. Blood samples for insulin-like growth factor I, free T4, and TSH were taken after an overnight fast, followed by an oral glucose tolerance test. Direct intraneural recordings of MSNA were performed with a tungsten microelectrode from the peroneal nerve. The hypopituitary subjects had markedly increased MSNA (54 +/- 4 bursts/min vs. 34 +/- 4 in controls; P < 0.002), which was not related to abdominal obesity or altered glucose metabolism. When assessed for the whole study group, MSNA was inversely correlated to serum insulin-like growth factor I (r = -0.59; P < 0.006) and TSH (r = -0.46; P < 0.04). MSNA was positively correlated to diastolic blood pressure (r = 0.80; P < 0.0005) in patients, but not in controls. The intense sympathetic discharge is suggested to be of central origin and may be an important underlying mechanism for the secondary hypertension and increased cardiovascular morbidity/mortality in this patient group.

Growth hormone (GH) therapy in GH-deficient adults influences the response to a dietary load of cholesterol and saturated fat in terms of cholesterol synthesis, but not serum low density lipoprotein cholesterol levels.

An increased dietary load of cholesterol (ch) and saturated fat increases serum low density lipoprotein ch (LDL-ch) levels. GH therapy in GH-deficient adults decreases serum LDL-ch levels. In the rat, GH is important for resistance to dietary cholesterol in terms of serum cholesterol levels. The aim of this study was to investigate the influence of GH on the effects of an increase in the intake of cholesterol and saturated fat on serum lipoproteins and markers for cholesterol synthesis in man. Six GH-deficient adults were given an isocaloric diet enriched in cholesterol and saturated fat for 17 days with and without GH therapy (1-1.5 U/day). Serum cholesterol, LDL-ch, apolipoprotein B (apoB), and apoA1 levels increased during the diet period with GH therapy and tended to increase during the diet period without GH. However, GH therapy did not influence the dietary effect on serum cholesterol, LDL-ch, apoA1, or apoB levels. Serum levels of triglycerides, very low density lipoprotein ch, high density lipoprotein ch, and apoE were not affected by diet or GH therapy. GH therapy increased serum lipoprotein(a) levels, but did not affect the response to diet. The serum total delta7-lathosterol/cholesterol ratio increased less during the diet period with GH therapy than during the diet period without GH. Serum 7alpha-hydroxy-4-cholesten-3-one levels tended to increase during both diet periods, but were not influenced by GH treatment. Serum plant sterol levels did not change. These results indicate that GH counteracts an increase in cholesterol synthesis induced by a high fat diet without affecting bile acid synthesis or sterol absorption. GH therapy did not have any major influence on the dietary effects on serum lipoprotein levels.

Treatment of adults with growth hormone (GH) deficiency with recombinant human GH.

In a double blind, cross-over placebo-controlled trial, we studied the effects of 26 weeks of replacement therapy with recombinant human GH on body composition, metabolic parameters, and well-being in 10 patients with adult-onset GH deficiency (GHD). All patients received appropriate thyroid, adrenal, and gonadal replacement therapy. The dose of recombinant human GH was 0.25-0.5 U/kg.week (0.013-0.026 mg/kg.day) and was administered sc daily at bedtime. One patient was withdrawn from the study because of edema and atrial fibrillation. Body composition was estimated with three independent methods: computed tomography, bioelectric impedance, and total body potassium combined with total body water assessments. The Comprehensive Psychological Rating Scale and the Symptom Check List-90 were used to assess any change in psychopathology. After 26 weeks of treatment, adipose tissue (AT) mass decreased 4.7 kg (P < 0.001). Subcutaneous AT decreased by an average of 13%, whereas visceral AT was reduced by 30%. Muscle volume increased by 2.5 kg (5%; P < 0.05). According to the four-compartment model derived from assessments of total body potassium and total body water, body cell mass and extracellular fluid volume increased significantly by 1.6 and 3.0 kg, whereas body fat decreased by 6.1 kg. Results obtained by the bioelectric impedance technique were similar. The mean (+/- SD) concentrations of insulin-like growth factor-I increased from 0.26 (0.06) at baseline to 2.56 (1.55) and 2.09 (1.03) kU/L after 6 and 26 weeks of treatment. Calcium and serum phosphate, osteocalcin, and procollagen-III concentrations were significantly higher, and intact PTH concentrations were reduced after 6 and 26 weeks of treatment, respectively. Total and free T3 concentrations were significantly increased after 6 and 26 weeks of treatment, whereas free T4 concentrations were reduced at 6 weeks, but after 26 weeks, free T4 concentrations had returned to pretreatment values. Finally, after 26 weeks of treatment, there was a decrease in the Comprehensive Psychological Rating Scale score (P < 0.05). The results show that GH replacement in GHD adults results in marked alterations in body composition, fat distribution, and bone and mineral metabolism and reduces psychiatric symptoms. Finally, we conclude that the observed beneficial effects of replacement therapy with GH are of sufficient magnitude to consider treatment of GHD adults.