Intestinal calcium absorption and bone metabolism in young adult men with childhood-onset growth hormone deficiency.

Suboptimal growth hormone (GH) replacement therapy during childhood is a major cause of osteopenia in young adults with childhood-onset GH deficiency (CO-GHD). This is primarily attributed to reduced bone formation in childhood. It is currently not known whether GHD also has adverse effects on bone metabolism in adult life. To examine the impact of GHD on calcium and bone metabolism in adults, we evaluated 50 men with CO pituitary failure at a mean age of 28.2+/-4.5 years, i.e., 8.8+/-4.1 years after the discontinuation of previous GH treatment for short stature. Thirty-three patients had multiple pituitary hormone deficiencies (MPHD) for which they received conventional replacement therapy, seventeen patients had isolated GHD (IGHD), and forty-nine age-matched men served as controls. Intestinal calcium absorption, serum calcium concentration, serum phosphate levels, and renal calcium and phosphate excretion were normal in IGHD and MPHD patients. IGHD patients had marginally elevated serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen (ICTP: 5.0+/-1.2 vs. 4.2+/-1.2 microg/l, p < 0.05), but other indices of bone turnover were normal. In contrast, MPHD patients had reduced levels of the carboxy-terminal propeptide of type I procollagen (PICP: 137+/-76 vs. 179+/-72 microg/l, p < 0.01), elevated serum ICTP levels (6.0+/-3.8 vs. 4.2+/-1.2 microg/l, p < 0.001), and reduced serum 1,25-dihydroxyvitamin D levels (55.1+/-16.7 vs. 73.0+/-23.0 pmol/l, p < 0.001). Multivariate regression analysis showed that the serum levels of bone resorption and bone formation markers in MPHD patients were correlated with the hydrocortisone, thyroxine, and testosterone replacement doses. There was no relationship with serum insulin-like growth factor I concentration. Panhypopituitary adults receiving conventional hormone replacement therapy are at risk to develop osteopenia either caused by reduced bone formation or by increased bone resorption activity. Predominantly, these abnormalities result from nonoptimal thyroid, gonadal, or adrenal hormone replacement therapy. GHD is not an important factor. In adults, GHD does not adversely affect intestinal calcium absorption or bone formation activity. Bone resorption activity may be slightly higher than normal, but the abnormality is too small to expect substantial bone loss as a consequence of GHD.

Growth hormone substitution in adult growth hormone-deficient men augments androgen effects on the skin.

OBJECTIVE: To assess whether growth hormone (GH) administration to adult GH-deficient men leads to increased sexual hair. The sexual hair scores are subnormal in these patients, even in the presence of normal serum androgen levels. PATIENTS: Forty-six adult men with childhood-onset of GH deficiency of whom 25 were androgen deficient and received replacement. DESIGN: Double-blind and placebo-controlled. Of the 46 patients, 33 started immediately with GH administration; the remaining 13 received placebo for the first 6 months followed by GH for the next 6 months. Sixty-one age-matched healthy men with normal height and serum concentrations of IGF-I served as a comparison group. MEASUREMENTS: Hair scores at 13 defined body regions were assessed before, and after 6 and 12 months of the intervention. At the same time levels of IGF-I, dehydroepiandrosterone sulphate, androstenedione, dihydrotestosterone (DHT), testosterone and sex hormone binding globulin (SHBG) were measured. From the latter two, the free androgen index (FAI) was calculated. RESULTS: Before GH administration, hair scores in the GH deficient patients were lower than in the comparison group. In the 33 men treated with GH from the beginning, there was an increase in hair scores after 6 months. The increase in hair scores was not seen during 6 months of placebo treatment. When the placebo group switched to GH administration, their hair scores had also significantly increased after 6 months of GH substitution therapy. Upon GH administration both levels of SHBG and testosterone/DHT declined while the FAI remained unchanged. CONCLUSION: GH substitution therapy to GH deficient men has an auxiliary effect on androgen action in the skin without an increase of the FAI.

Histomorphometric analysis of bone mass and bone metabolism in growth hormone deficient adult men.

Transiliac bone biopsies were obtained from 36 growth hormone (GH) deficient men (mean age +/- SD, 28 +/- 4 years), of which 13 had an isolated GH deficiency and 23 had partial or complete hypopituitarism. The latter group was adequately substituted for the pituitary hormone deficiencies other than GH. Static histomorphometry was compared with eight controls, and dynamic histomorphometry was compared with six healthy men matched for age. Mean trabecular bone volume was not decreased and bone volume was high (> 30%) in ten patients. Osteoid thickness and mineralization lag time were slightly although not significantly higher than in controls. Osteoid surface, mineralizing surface and bone formation rate tended to be lower than in the controls. The eroded surface was significantly higher (p < 0.002) in the GH deficient patients. The results demonstrate that GH deficient patients do not show trabecular osteoporosis. The increased eroded surface together with normal to increased bone volume and bone surface suggests a prolonged reversal phase or a less sufficient coupling phenomenon.

Changes in subcutaneous and visceral fat mass during growth hormone replacement therapy in adult men.

OBJECTIVES: To assess the degree of subcutaneous and intraabdominal fat accumulation in growth hormone (GH) deficient adult men, and to evaluate the lipolytic effects of GH replacement therapy. DESIGN: Placebo-controlled, double-blind, dose-response study. All patients, including those initially starting on placebo, received GH for a period of one year. SUBJECTS: 46 adult men (mean age 28.0 +/- 4.5 y) with childhood-onset GH deficiency (GHD). MEASUREMENTS: Subcutaneous fat mass and fat distribution was assessed by measurement of skinfold thicknesses at seven different sites. Intraabdominal fat mass was assessed by computerized tomography (CT). Reference values were obtained from age- and sex-matched controls with a normal body mass index. RESULTS: The sum of skinfolds (SKFs) was 75% (95% CI: 52-98%) higher, and intraabdominal fat area was 84% (95% CI: 45-122%) greater in GHD patients than in age- and sex-matched controls. Patients with multiple pituitary hormone deficiencies (MPHD, n = 30), who were all receiving conventional hormone replacement therapy, were more obese than patients with isolated GHD (IGHD, n = 16). This difference was attributed to a more severe impairment in GH secretion, as well as to the lower androgen levels in patients with MPHD. GH treatment was associated with a gradual decline in subcutaneous fat that continued for approximately six months. Thereafter, a new steady-state was reached. The GH-induced decline in subcutaneous and intraabdominal fat was dose-dependent (r = 0.84, p < 0.001 and r = 0.52, p < 0.001, respectively). The efficacy of GH treatment was similar to IGHD and MPHD patients. Optimal GH replacement, defined as treatment resulting in normalization of serum insulin-like growth factor-I (IGF-I) concentration, was achieved in 25 patients. In this subgroup the sum of SKFs decreased by 27% (95% CI: 22-32%) and intraabdominal fat was reduced by 47% (95% CI: 38-57%). CONCLUSION: We conclude that subcutaneous as well as intraabdominal fat mass are abnormally high in GHD men, and that GH treatment with doses within the physiological range profoundly reduces the sizes of both fat compartments. In addition, GH replacement therapy was found to be equally effective in men with IGHD as in those with MPHD.

Cognitive impairments and mood disturbances in growth hormone deficient men.

In order to establish whether reported psychological complaints in hypopituitary adults are related to growth hormone (GH) deficiency or other pituitary hormone deficiencies, emotional well-being and cognitive performance were evaluated in 31 men with multiple pituitary hormone deficiencies (MPHD) and in 17 men with isolated growth hormone deficiency (IGHD). Assessments included evaluation of somatic and psychological complaints, depression, fatigue, vigor, tension, state and trait anxiety, iconic memory, short-term memory, long-term memory and perceptual-motor skill. The control group consisted of 41 healthy men, matched for age. Growth hormone secretion was more severely impaired in MPHD than in IGHD patients. Despite oral replacement therapy, MPHD patients also had lower serum testosterone levels than IGHD subjects. The MPHD patients were found to have lower vigor scores, higher state anxiety scores, worse perceptual-motor skill and worse memory performance than controls. In contrast, IGHD patients only showed subnormal memory performance. It was concluded, therefore, that the cognitive impairment in both MPHD and IGHD was related to GH deficiency. The subnormal vigor scores in MPHD patients were attributed to the reduced testosterone levels. The worse perceptual-motor skill in MPHD patients might be related specifically to ACTH deficiency. Finally, the higher state anxiety in MPHD was attributed to a low self-esteem, which may be the psychological consequence of the hypogonadal appearance these patients have. We conclude that, from a psychological point of view, MPHD and IGHD adult patients are quite distinct groups.

Monitoring of growth hormone replacement therapy in adults, based on measurement of serum markers.

The optimal dose for GH replacement therapy in GH-deficient (GHD) adults is not known, nor is there a consensus as to which method is the most appropriate for the monitoring of treatment. To establish a general guideline for GH replacement therapy in adults, we evaluated the relationship between the administered GH dose and the achieved serum levels of three GH-dependent serum markers. Serum levels of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were measured in 46 GHD men participating in a 1-yr, double blind, and placebo-controlled dose-response study. The doses of recombinant human GH ranged from 0.33-3.0 IU/m(2)-day. During GH treatment, dose reduction was necessary because of side-effects in 18 of 46 patients, i.e. in 18% of the patients receiving a maintenance dose of 1 IU/M(2)-day, in 35% of the patients receiving a dose of 2 IU/m(2)-day, and in 67% of the patients receiving a dose of 3 IU/M(2)-day. In the untreated state, serum levels of all three markers were below the normal range in 90% of the patients. The rise in serum marker concentrations during the first month of treatment was dose dependent. Significant increases in IGF-I, IGFBP-3, and ALS levels were observed with a dose as low as 0.33 IU/M(2)-day. The minimal GH dose required for normalization of the serum IGF-I concentration was 0.66 IU/M(2)-day, and it was 1.0 IU/M(2)-day for ALS and IGFBP-3. In patients receiving 2.0 IU/M(2)-day, the mean serum IGF-I concentration rose to an abnormally high level, whereas at this dose, the mean IGFBP-3 and ALS levels were not different from normal. The lower sensitivity of IGFBP-3 and ALS to GH doses in the high range was also apparent during long term treatment. The number of patients who developed IGFBP-3 or ALS levels that exceeded the upper normal limit was substantially smaller than the number of patients with elevated IGF-I concentrations (2, 8, and 19 of 46 patients, respectively). In conclusion, serum IGF-I appears to be the preferred biochemical marker for the detection of GH excess in adults receiving GH replacement therapy, because it is more sensitive than IGFBP-3 and ALS to GH doses in the high range. If normalization of the serum IGF-I concentration is taken as the criterion for optimal GH replacement therapy, the predicted optimal GH dose for GHD men 20 - 40 yr old is 1.4 IU/M(2)-day, and the 95% confidence interval is 1.2-1.6 IU/M(2)-day.

The optimal growth hormone replacement dose in adults, derived from bioimpedance analysis.

The prevalence of clinical signs and symptoms related to fluid retention is high in most studies evaluating the efficacy of GH treatment in GH-deficient (GHD) adults. This may be a consequence of supraphysiological GH replacement. To examine whether fluid retention is a dose-related phenomenon, we evaluated the impact of various GH substitution doses on body fluid status in 46 GHD men participating in a 1-yr, double blind, and placebo-controlled study. The patients were randomized to receive either placebo (n = 13) or GH in a dose of 1 (n = 11), 2 (n = 10), or 3 (n = 12) IU/m2.day, respectively. Treatment was started at one third of the predetermined dose and was subsequently increased by another third every month until the maintenance dose was reached. Tissue hydration was assessed by means of electrical impedance measurements. Normal values were obtained from 128 age- and sex-matched controls. In the untreated GHD state, whole body resistance was abnormally high (observed, 642 +/- 82 omega; predicted, 550 +/- 31 omega; P < 0.001). This was mainly caused by an increase in specific resistance of the lean body as a consequence of a reduction in extracellular water (ECW). The first month of GH treatment was associated with a sharp decline in electrical resistance that was attributed to an increase in ECW. Whole body resistance reached its nadir after 3 months of treatment (517 +/- 72 omega, i.e. 19.6 +/- 6.5% lower than before treatment; P < 0.001) and did not change significantly thereafter. The GH-induced changes in body resistance were dose dependent. A significant decrease was observed with a dose as low as 0.33 IU/m2.day (P < 0.005). However, whole body resistance remained higher than normal in patients receiving less than 0.67 IU/m2.day (P = 0.05). Abnormally low resistance values, indicative of overhydration, were observed in patients receiving doses equal to or higher than 2 IU/m2.day (P < 0.005). Regression analysis of the pooled data showed that GH replacement in a dose of 1.10 IU/m2.day (95% confidence interval, 0.85-1.45 IU/m2.day) resulted in a normalization of whole body resistance. In conclusion, GH replacement therapy in adults rapidly corrects the preexisting deficit in ECW. This rehydration process is dose dependent and may result in a substantial weight gain.(ABSTRACT TRUNCATED AT 400 WORDS)

Consequences of childhood-onset growth hormone deficiency for adult bone mass.

To assess the implications of prolonged growth hormone deficiency (GHD) for the acquisition and maintenance of bone mass, bone mineral density (BMD) was measured in 70 adult males (mean age 26.7 +/- 4.5 years) with childhood-onset GHD, 7.4 +/- 4.2 years after discontinuation of previous GH therapy. Because most of these patients were short (mean height 165.8 +/- 6.6 cm), the influence of body height on standard BMD measurements, conventionally reported as the areal density (BMDarea, expressed in g/cm2), was analyzed in a group of age-matched healthy males. In GHD patients, BMDarea was significantly reduced at the lumbar spine (Z score -1.59 +/- 1.08, p < 0.001) as well as at the nondominant hip (Z score -1.18 +/- 0.95, p < 0.001). The reduction in BMDarea was similar for patients with isolated GHD (N = 25) and those with combined deficiencies of GH and luteinizing hormone (N = 40). In patients and controls, BMDarea was positively correlated with body height, a relation that was attributed to skeletal size. Bone dimensions were significantly smaller in patients than in controls, and therefore it was hypothesized that the difference in areal density between patients and controls might be confounded by differences in bone size. Measured bone mineral content corrected for the estimated bone volume (BMDvolume, expressed in g/cm3) remained significantly reduced (Z score: lumbar spine, -0.90 +/- 1.08, p < 0.001; femoral neck, -0.74 +/- 1.00, p < 0.001), but the differences between GHD patients and controls were less than indicated by BMDarea (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum lipid levels in growth hormone-deficient men.

To evaluate the impact of growth hormone deficiency (GHD) on lipid metabolism, serum lipid and apolipoprotein concentrations were measured in 64 GHD adult males (mean age, 27.1 +/- 4.7 years). Results were compared with those obtained from an age- and sex-matched control group. Total cholesterol, low-density lipoprotein (LDL) cholesterol, and apolipoprotein (apo) B levels were significantly higher in GHD patients (P < .001). In 14 patients (23%), total cholesterol concentration exceeded the 95th percentile for healthy adults. Total and LDL cholesterol were inversely related to plasma insulin-like growth factor-I (IGF-I). Apo B also tended to be negatively correlated with IGF-I; however, statistical significance was not reached (P = .054). High-density lipoprotein (HDL) cholesterol and plasma triglyceride concentrations were within normal limits, whereas apo A-1 and A-2 levels were only slightly different from normal. We conclude that GHD in adulthood is associated with mild hypercholesterolemia due to an increased LDL cholesterol level. An inverse relationship was established between LDL cholesterol concentration and GH secretory status.

Body composition in adult growth hormone-deficient men, assessed by anthropometry and bioimpedance analysis.

Anthropometry and bioimpedance analysis (BIA) were used to assess body composition in 42 GH-deficient (GHD) adult males (mean age, 27.2 +/- 4.7 yr). During childhood, all patients had received GH treatment for a mean period of 8.4 +/- 3.8 yr. At the start of this study, GH therapy had been discontinued for a mean period of 7.5 +/- 4.5 yr. Eighteen patients had isolated GH deficiency (I-GHD). Twenty-four patients had multiple pituitary hormone deficiencies (M-PHD), substituted adequately. Compared to age- and sex-matched controls, the sum of skinfolds measured at 7 different sites was significantly higher in I-GHD and M-PHD patients [controls, 73.1 +/- 25.4 mm; I-GHD patients, 102.1 +/- 37.7 mm (P less than 0.001); M-PHD patients, 126.8 +/- 35.4 mm (P less than 0.001)]. The increase in sc fat deposition was most pronounced on the trunk, particularly in the breast and abdominal area. Total body muscle mass was significantly lower in GHD patients (P less than 0.001). In patients, body muscle mass and plasma somatomedin-C level were positively correlated (r = 0.43; P less than 0.005). Total body resistance measured by whole body BIA was significantly higher in the patient group and was negatively correlated with plasma somatomedin-C (r = -0.53; P less than 0.001). The high resistance values observed in GHD patients could only in part be explained by their lower lean body mass. The most important cause, however, was an increase in specific electrical resistance of the lean body mass (LBM), reflecting relative dehydration. We conclude that GH deficiency in adult males is associated with an increase in sc fat and a decrease in body muscle mass. In addition, there is a qualitative change in LBM. The BIA data indicate that in these patients, the hydration state of the LBM is lower than normal, due to a decrease in extracellular water.

Influence of concentration and injection volume on the bioavailability of subcutaneous growth hormone: comparison of administration by ordinary syringe and by injection pen.

In order to study whether the bioavailability of subcutaneously injected growth hormone (GH) is dependent on the concentration/volume injected, the relative GH bioavailability was evaluated in 14 GH-deficient patients. In a cross-over study the patients received, in random order two separate subcutaneous GH injections (Norditropin) 4 IU administered by means of an ordinary syringe (4 IU ml) and an injection pen with cartridge (Nordiject 24) (12 IU/ml). Blood samples were drawn over a 14 hr period and assayed for serum concentrations of GH and IGF-I. The mean value (+/- S.D.) of the relative absorption fraction (Fpen/sy) was 1.09 +/- 0.39. Mean values of Cmax were 8.6 ng/ml +/- 4.8 and 8.3 ng/ml +/- 7.5 for syringe and pen respectively. Corresponding values for Tmax were 311 min. +/- 131 for syringe and 309 min. +/- 104 for pen. Although a considerable interindividual variation was seen, the relative absorption fraction did not differ significantly from 1 (2 P = 0.78). Further there was no significant difference in neither Cmax (2 P = 0.39) nor Tmax (2 P = 0.55). IGF-I serum profiles tended to be higher following syringe compared to pen injection (2 P = 0.054). On the basis of this study we conclude that in this dosage regimen. GH bioavailability following pen injection equals that of injection by syringe (i.e. no effect of a three fold increase/decrease in GH concentration/volume respectively).

Diagnosis of IgE-mediated allergy in the upper respiratory tract.

A statistical analysis was made of data concerning diagnosis of IgE-mediated allergy in the upper respiratory tract in 292 patients. A study was made of: skin test, total and specific IgE (RAST), X-sinus, red blood investigation, and cytology of nasal smear. It appears that screening for the presence of an IgE-mediated allergy in the upper respiratory tract can be performed efficiently with a limited number of skin tests (rye grass, timothy, birch, house dust mite and cat). In this study a greater number of skin tests (15 instead of 5) yielded little additional information (in 2% of the patients). A rather poor correlation between skin test and RAST was found.

[The diagnosis of IgE-mediated allergy of the upper airways]. / Diagnostiek van IgE-gemedieerde allergie van de bovenste luchtwegen.

A statistical analysis was made of data concerning diagnosis of IgE-mediated allergy in the upper respiratory tract in 292 patients. It appears that screening for an IgE-mediated allergy can be performed with a limited number of skin tests (rye grass, timothy, birch, house dust mite and cat). In this study a larger number of skin tests (15 instead of 5) and investigation of specific IgE (RAST) yielded little additional information (in 2% and 3% of the patients, respectively). When indicated, an extended series of skin tests, immuno-assay (total IgE and specific IgE) and eosinophil counts in the serum and nasal smear should be performed.