Efficacy and safety of individualized growth hormone treatment in adult Japanese patients with growth hormone deficiency

OBJECTIVE: The aim of the study was to evaluate the efficacy and safety of growth hormone (GH) treatment in Japanese adult patients with GH-deficiency. In the extension of the efficacy study, the effect of individualized-dosing (ID), based on insulin-like growth factor-I (IGF-I) levels, and fixed-dose (FD) GH regimens on body composition, were compared in Japanese GH-deficient adults. DESIGN: Randomized, double-blind (DB), placebo-controlled, 24-week treatment period followed by 48-week, open-label study in 43 endocrinology clinics in Japan. Patients received DB treatment with GH (0.012 mg/kg/day; n=57) or placebo (n=60) followed by open-label GH in an ID (n=75) or FD (0.012 mg/kg/day; n=38) regimen. SUBJECTS: Adult Japanese GH-deficient patients (peak GH<3 ng/mL). MEASUREMENTS: Trunk and total body fat (BF), lean body mass (LBM), and adverse events were determined. RESULTS: Percentage trunk fat was reduced significantly more in GH- than in placebo-treated patients at 24 weeks (-16.2 vs. 1.7%, p<0.0001). Open-label treatment with an ID or FD GH regimen provided similar reductions in percentage trunk fat (-8.12 vs. -9.35%), and total BF (-0.92 vs. -0.70 kg) and a comparable increase in LBM (1.032 vs. 0.97 kg). Mean+/-SD GH doses (mg/kg/day) at 48 weeks were significantly lower with the ID GH regimen (ID, 0.0082+/-0.0050; FD, 0.0095+/-0.0033; p<0.05). The safety profile was comparable between ID and FD groups. CONCLUSIONS: Treatment with GH was associated with a significant reduction in trunk fat and improvement in serum lipid profile in Japanese adult GH-deficient patients. The improvement in body composition and tolerability were comparable between ID and FD GH regimens despite a significantly lower daily GH dose with the ID regimen.     

Monitoring serum insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and leptin during growth hormone treatment for disordered growth

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS: The study included 31 patients, grouped as (1) GHD (n = 20) and (2) non-GHD (Turner syndrome n = 7; Noonan syndrome n = 4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4+/-2.5 vs. -1.8+/-1.0; P<0.001). IGF-I (-1.8 SDS +/- 2.2) and IGFBP-3 (-1.1 SDS +/- 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS +/- 1.4) while IGFBP-3 (1.1 SDS +/- 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0. 77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 microg/l; median after 12 months treatment 2.4 microg/l; P = 0.02) but not the non-GHD (median before treatment 3.0 microg/l; median after 12 months treatment 2.6 microg/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during long-term GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.     

Quantitation of urinary somatomedin-C and growth hormone in preterm and fullterm infants and normal children

Urinary GH and somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) excretion were measured in 12-h urine collections obtained from 43 infants (27 stable preterm infants and 16 healthy fullterm infants) and 31 normal children, aged 3-17 yr. Urinary Sm-C/IGF-I was excreted as the free hormone, since no binding of radiolabeled Sm-C/IGF-I to any urine protein with a mol wt similar to those described for plasma Sm-C/IGF-I-binding proteins was found. The preterm infants excreted significantly more urinary GH [13.5 +/- 2.1 (+/- SE) ng/kg.12 h] than either the fullterm infants (5.3 +/- 1.6 ng/kg.12h) or the children (0.27 +/- 0.02 ng/kg.12 h; P less than 0.01). The mean urinary Sm-C/IGF-I excretion in the preterm infants (98.9 +/- 7.5 mU/kg.12 h) was comparable to that in fullterm infants (87.6 +/- 9.7 mU/kg.12 h); both groups excreted significantly more urinary Sm-C/IGF-I than children (28.4 +/- 2.1 mU/kg.12 h; P less than 0.01). The group differences were similar when the results were expressed in terms of creatinine excretion. Urinary GH excretion correlated positively with urinary Sm-C/IGF-I excretion (r = 0.68). The higher output of these peptides in rapidly growing infants and their positive correlation in urine provide additional support for the Sm hypothesis.     

Dietary carbohydrate content determines responsiveness to growth hormone in energy-restricted humans

To determine if diet composition influences responses to GH, we fed 11 obese women diets containing 12 Cal/kg ideal BW (IBW) for 2 5-week study intervals. Nonprotein calories were supplied to 6 subjects as 72% carbohydrate (high carbohydrate diet), and 5 subjects received 80% of their nonprotein calories as lipid (high lipid diet). Protein intake was constant (1.0 g/kg IBW) in both groups. During 1 study interval we gave injections of GH (0.1 mg/kg IBW) every other day for 3 weeks (weeks 2-4), and in the other interval injections of vehicle were given. Subjects ingesting the high carbohydrate diet excreted significantly less urinary nitrogen [660.2 +/- 124.1 mmol/day (mean +/- SD)] than those who received high lipid (794.2 +/- 198.5 mmol/day; P less than 0.001), and GH injections reduced nitrogen excretion in the high carbohydrate subjects (532.8 +/- 123.8 mmol/day), but not in the high lipid subjects (743.7 +/- 126.6 mmol/day). The subjects receiving the high carbohydrate diet had a significant increase in serum insulin-like growth factor-I (IGF-I; from 36.2 +/- 9.7 to 55.9 +/- 6.6 nmol/L) and urinary C-peptide excretion (from 43.9 +/- 25.6 to 60.8 +/- 29.4 nmol/day) in response to GH. The IGF-I response attenuated slowly over the 3-week treatment interval. On the other hand, the high lipid group had lesser increases in IGF-I (from 31.0 +/- 6.5 to 41.7 +/- 8.8 nmol/L) and C-peptide excretion (from 24.3 +/- 28.9 to 29.8 +/- 32.8 nmol/day), and IGF-I concentrations declined to control values after only 5 days of GH injection. We believe that this initial IGF-I response was due to an antecedent 35-Cal balanced diet. The mean increment in serum FFA 4 h after GH injection was significantly less in subjects fed the high lipid diet (0.53 +/- 0.40 meq/L) than in those fed the high carbohydrate diet (0.83 +/- 0.43 meq/L). GH injections produced more body fat loss than injections of vehicle whether expressed as percent body fat lost (GH, 3.7 +/- 1.0%; vehicle, 2.8 +/- 0.7%, P less than 0.05) or as the fraction of weight lost as fat (fat loss/weight loss; GH, 0.81 +/- 0.13; vehicle, 0.64 +/- 0.08; P less than 0.005). There was an inverse correlation between the percentage of body fat lost and mean urinary C-peptide excretion during GH injections (r = -0.70; P less than 0.05), suggesting that stimulation of insulin secretion by GH might antagonize the tendency of GH to promote fat loss.(ABSTRACT TRUNCATED AT 400 WORDS)     

Early growth of infants of HIV-infected and uninfected Zambian women

OBJECTIVE: Parental HIV infection may affect even those exposed children who remain uninfected. We investigated early growth, an indicator of overall health, of infants born to Zambian mothers recruited for a study of breastfeeding and postpartum health. METHODS: HIV-infected and uninfected women in Lusaka were followed regularly from late pregnancy to 16 weeks postpartum. Infant weight and length were measured at birth, 6 and 16 weeks. Infant HIV status could not be specifically determined in this cohort so comparisons were between all infants of HIV-uninfected mothers (n = 184) and those infants of HIV-infected mothers who were known to be alive and showed no clinical evidence of HIV infection at age 2-4 years (n = 85). RESULTS: Most infants were exclusively or predominantly breastfed until 16 weeks. At all time points infants of HIV-infected mothers tended to have lower weight and length standard deviation (Z) scores (significant for weight at 6 weeks; P = 0.04), even after adjustment for their lower gestational age at birth, compared with infants of uninfected mothers. In multivariate analyses the major factors affecting weight or length at 6 or 16 weeks of age were birth weight or length, and maternal subclinical mastitis, primiparity and weight during pregnancy. CONCLUSIONS: Early growth of infants of HIV-infected mothers is less than that of uninfected mothers, in part associated with subclinical mastitis, and this effect cannot be overcome with intensive support of mothers to follow international recommendations regarding exclusive breastfeeding.     

The effect of four weeks of supraphysiological growth hormone administration on the insulin-like growth factor axis in women and men. GH-2000 Study Group

Measurements of serum insulin-like growth factor I (IGF-I) and related markers are routinely used in the diagnosis and treatment of GH deficiency and excess. The validity of these markers for assessment of exogenous GH exposure in healthy adults is, however, unknown. We therefore conducted a double blind, placebo-controlled GH treatment trial in 99 healthy subjects [49 women and 50 men; mean +/- SE age, 25.6+/-0.6 (women)/25.7+/-0.6 yr (men)]. Blood was collected weekly during a 4-week treatment period (days 1-28), and the subjects were subsequently followed for additional 8 weeks (days 29-84). The treatment arms included: I) 0.1 IU/kg x day GH (n = 30; GH 0.1), II) 0.2 IU/kg x day GH (n = 29; GH 0.2), and III) placebo (n = 40). At baseline no gender-specific differences existed, except that the acid-labile subunit (ALS) levels were higher in females. Serum insulin-like growth factor I (IGF-I) levels in males receiving GH increased significantly through day 42 with no significant difference between the 2 doses. The absolute IGF-I response was significantly lower in females, and there was a clear dose-response relationship. ALS levels in males increased through day 30 (P < 0.001). In females ALS levels were only modestly increased on day 28 compared with those in the placebo group (P < 0.02). IGF-binding protein-3 (IGFBP-3) levels in males increased significantly in the GH 0.1 and the GH 0.2 groups on day 30 (P < 0.03), whereas no solid IGFBP-3 increase was detected in females. IGFBP-2 levels decreased insignificantly during GH exposure in both genders. A gender-specific upper normal range for each analyte was arbitrarily defined as 4 SD above the mean level at baseline. On the basis of IGF-I levels alone, GH exposure in the GH 0.2 group was detected in 86% of the males and in 50% of the females on day 21. On day 42 GH exposure was only weakly detectable in males and was not detectable in females. We conclude that 1) males are significantly more responsive than females to exogenous GH; 2) the increase in IGF-I is more robust compared with those in IGFBP-3 and ALS; 3) IGFBP-2 changes very little during GH treatment; and 4) among IGF-related substances, IGF-I is the most specific marker of supraphysiological GH exposure.     

The interrelationship between and the regulation of hepatic growth hormone receptors and circulating GH binding protein in the pig.

We evaluated the interrelationship between, and regulation of, the hepatic growth hormone receptor and serum GH binding protein (GH BP) in pigs treated with recombinant porcine growth hormone (rpGH). Infant and pubertal male pigs (N = 5 per group) received either rpGH 0.15 mg/kg daily or diluent intramuscularly for 12 days. Somatic growth, serum IGF-I and GH BP and [125I]bovine GH (bGH) binding to MgCl2-treated hepatic membrane homogenates were examined. Marked age-related increases were seen in serum GH BP (p less than 0.001) and [125I]bGH binding to hepatic membranes (p less than 0.001). GH BP was increased in rpGH treated animals (p = 0.03), from 13.8 +/- 1.2 (mean +/- 1 x SEM) (controls) to 17.8 +/- 2.0% in infants, and from 35.2 +/- 2.6 (controls) to 41.8 +/- 3.4% in pubertal animals. [125I]bGH binding to hepatic membranes was also increased by rpGH treatment (p less than 0.05), from 7.0 +/- 1.6 (controls) to 15.4 +/- 3.6% in infants and from 53.7 +/- 7.1 (controls) to 65.1 +/- 11.8% in pubertal animals. No significant interaction between age and treatment was seen. Overall, serum GH BP correlated significantly with [125I]bGH membrane capacity (r = 0.82, p less than 0.001), with a correlation of r = 0.83 in the infant animals but no significant correlation in the pubertal animals considered alone (r = 0.13). Serum IGF-I correlated significantly with serum GH BP (r = 0.93, p less than 0.001) and [125I]bGH membrane binding capacity (r = 0.91, p less than 0.001). These observations suggest that serum GH BP levels reflect major changes of hepatic GH receptor status.(ABSTRACT TRUNCATED AT 250 WORDS)     

Route of estrogen administration helps to determine growth hormone (GH) replacement dose in GH-deficient adults

We prospectively studied two groups of GH-deficient patients during GH therapy based upon exposure of the liver to elevated (oral estrogen) or not elevated (endogenous or transdermal) sources of estrogen. We wondered whether higher concentrations of estrogen at the liver level (oral estrogen) might inhibit insulin-like growth factor I (IGF-I) secretion and alter exogenous GH requirements. In this study we compared GH replacement requirements in these two groups of women as well as with GH-treated adult hypopituitary males. The final GH dose was based upon maintenance IGF-I levels in the mid- to high normal range adjusted for age and sex or symptom tolerance. Each group [women taking oral estrogen (n = 12), women not taking oral estrogen (n = 13), and men (n = 12)] was similar in age and final IGF-I concentration. Women taking oral estrogen required 10.6 +/- 0.7 microg/kg x day or 867 +/- 45 microg/day GH, women not taking oral estrogen required 5.0 +/- 0.7 microg/kg x day or 424 +/- 57 microg/day, and men required 4.1 +/- 0.6 microg/kg x day or 376 +/- 49 microg/day to achieve similar IGF-I concentrations. GH requirements in men were not different from those in women not taking oral estrogen, but the GH requirements in both groups were significantly different from GH requirements in women taking oral estrogen. These observations may be useful in anticipating appropriate starting and final doses of GH in adult hypopituitary patients.     

Effect of L-arginine supplementation on secretion of human growth hormone and insulin-like growth factor in adults

Based on presumptions that the infusion of amino acids can augment the release of human growth hormone (hGH) and that this metabolism is related with secretion of insulin-like growth factor I (IGF-I), the purpose of this study was to verify the effect of L-arginine supplementation on GH and IGF-I in adults. Seventeen male individuals participated on the study and were randomized to receive L-arginine (n= 10) or placebo (n= 7), seven grams per day for seven days. Before and after the supplementation period, the volunteers realized blood collection in fasting to verify both GH and IGF-I levels, as well as urine collection to verify urea excretion. At the end of the experimental period, it was verified that the group that received L-arginine augmented the urea in urine excretion (to 2684.1 +/- 475.2 mg/dl from 2967.2 +/- 409.7 mg/dl, p= 0.002), therefore it did not alter significantly the release of hormones evaluated. The group which received placebo did not alter significantly any evaluated parameters. The L-arginine supplementation during seven days was ineffective to augment both GH and IGF-I release in individual male adults.     

Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor, and delivery

We previously reported that immunoreactive corticotropin-releasing hormone (CRH) is present in human placenta and third trimester maternal plasma, and that such material is very similar to rat CRH and the predicted structure of human CRH. We suggested that maternal plasma immunoreactive CRH may be of placental origin. To further investigate this possibility, we measured plasma immunoreactive CRH in women during pregnancy, labor, and delivery and 1 and 2 h postpartum, and in nonpregnant women. Umbilical cord plasma and placental CRH concentrations were also measured. In the first trimester of pregnancy, the mean maternal plasma level was 5.9 +/- 1.0 pg (+/- SEM)/ml (n = 24), not significantly different from that in 10 nonpregnant women (5.8 +/- 0.8 pg/ml). Plasma CRH concentrations progressively increased during pregnancy (second trimester, 35.4 +/- 5.9 pg/ml (n = 39); early third trimester (28-34 weeks), 263 +/- 41 pg/ml (n = 14); late third trimester (35-40 weeks), 800 +/- 163 pg/ml (n = 20)]. There was a significant correlation between maternal plasma CRH levels and weeks of pregnancy. Plasma CRH concentrations were further elevated (2215 +/- 329 pg/ml; n = 9). During early labor, peaked at delivery (4409 +/- 591 pg/ml; n = 28), and declined rapidly after delivery [1 h postpartum, 1042 +/- (353 pg/ml (n = 13); 2 h postpartum, 346 +/- 91 pg/ml (n = 13)]. There was a significant correlation (r = 0.562; P less than 0.01) between matched maternal plasma and placental CRH concentrations. The mean umbilical cord plasma CRH level (50.6 +/- 6.1 pg/ml; n = 28) was much lower than that in the mother at the time of delivery. Umbilical venous plasma CRH levels were significantly greater than those in simultaneously obtained umbilical arterial plasma (70.8 +/- 11.3 and 41.8 +/- 4.9 pg/ml, respectively; n = 11). There was a significant correlation (r = 0.384; P less than 0.05) between maternal and fetal CRH concentrations. Gel filtration of plasma obtained from women during the third trimester, at delivery, and early postpartum and placental extracts revealed two major peaks of immunoreactive CRH: a high mol wt peak and one at the elution position of rat CRH. In contrast, only rat CRH-sized material was detected in plasma from nonpregnant women and umbilical cord plasma. Maternal plasma immunoreactive CRH-sized material stimulated ACTH release from anterior pituitary tissue in a dose-dependent manner and was equipotent with rat CRH.(ABSTRACT TRUNCATED AT 400 WORDS)     

Increases in circulating insulin-like growth factor I levels by the oral growth hormone secretagogue MK-0677 in the beagle are dependent upon pituitary mediation

It has been well established that the spiroindoline sulfonamide MK-0677 stimulates GH secretion from the pituitary both in vitro and in vivo. MK-0677 has also been shown to increase serum insulin-like growth factor I (IGF-I) and cortisol levels in vivo; these increases are assumed to be driven by the increased serum GH and ACTH levels, respectively. However, such increases could also be due to a direct stimulatory action of MK-0677 at the level of the liver and adrenal cortex. To address this possibility, we investigated whether MK-0677 increased IGF-I and cortisol levels in hypophysectomized dogs. Baseline GH, IGF-I, and cortisol responses to MK-0677 (1 mg/kg, orally) were initially determined. Hypophysectomy (hypox; n = 7) or sham surgery (sham; n = 5) was then carried out. Six days postsurgery, the GH and cortisol responses to MK-0677 were reevaluated in each dog. In addition, each dog was treated with porcine GH (PST; 0.1 IU/kg, s.c.) to confirm the responsiveness of the GH-IGF-I axis. The mean peak GH increases in response to MK-0677 in the presham dogs (83.7 +/- 19.2 ng/ml), post-sham dogs (108 +/- 26.2 ng/ml), and pre-hypox dogs (121.2 +/- 13.6 ng/ml) were not significantly different. Mean peak GH levels were unchanged after MK-0677 administration in the hypox dogs (2.3 +/- 0.7 ng/ml). Before surgery, serum IGF-I levels increased to 243 +/- 27 and 224 +/- 47 ng/ml in the sham and hypox groups, respectively, after MK-0677 administration. Surgery was associated with a marked (> or =50%) decrease in serum IGF-I levels. MK-0677 administration increased IGF-I levels in the sham dogs from 78 +/- 14 to 187 +/- 31 ng/ml, whereas IGF-I levels remained unchanged (17.7 +/- 2.4 ng/ml) in the-hypox dogs. PST treatment increased IGF-I levels in the sham dogs from 162 +/- 30 to 325 +/- 32 ng/ml. In the hypox dogs PST treatment restored IGF-I to physiological levels (from 17.7 +/- 2.4 to 199 +/- 41 ng/ml). Cortisol was increased after MK-0677 administration 3.7-fold in the pre-sham, 3.6-fold in the post-sham, and 3.6-fold in the pre-hypox dogs, but no increase was seen in the post-hypox dogs. ACTH GEL administration (2.2 U/kg, i.m.) to hypox dogs returned cortisol to normal physiological levels, demonstrating the functional integrity of the adrenal cortex. This study demonstrates that the GH secretagogue MK-0677 does not directly stimulate an increase in serum IGF-I or cortisol levels, but depends upon the presence of an intact pituitary.     

Treatment of obese, diet-restricted subjects with growth hormone for 11 weeks: effects on anabolism, lipolysis, and body composition

We found in a previous study that injections of GH for 3 weeks caused nitrogen conservation despite restriction of intake to 24 Cal (100 kJ)/kg ideal BW (IBW). To determine the effects of longer periods of treatment and further caloric restriction on nitrogen balance, lipolysis, and body composition, 20 obese (30-67% over IBW) subjects (16 women and 4 men; 20-54 yr old) were fed a diet of 18 Cal (75 kJ)/kg IBW with 1.2 g protein/kg IBW daily for 13 weeks. During weeks 2-12, 10 subjects received injections of recombinant methionyl GH (0.1 mg/kg IBW every other day), and the other 10 sex-, age-, and weight-matched subjects were given injections of saline. There were no significant differences between the two groups in total weight loss [GH, 13.9 +/- 3.0 (+/- SD) kg; saline, 15.2 +/- 3.8 kg ) or the percentage of body fat lost (GH, 8.1 +/- 2.4%; saline, 7.5 +/- 1.5%), although GH injection caused a significant acute increment in serum FFA concentrations (GH, 0.53 +/- 0.37 mmol/L; saline, 0.08 +/- 0.22 mmol/L; P less than 0.001) throughout the study. This acute lipolytic response to GH decreased significantly, from 0.86 +/- 0.32 mmol/L on day 1 of GH treatment to 0.35 +/- 0.41 mmol/L by day 35 of GH injection (P less than 0.01). Nitrogen balance was significantly more positive in the group receiving GH during the first 33 days of the GH injection period [GH, +0.07 +/- 1.82 g/day (+5.0 +/- 130.0 mmol/day); saline, -1.91 +/- 1.10 g/day (-136.3 +/- 78.5 mmol/day); P less than 0.001]. During the last 44 days of GH injection, however, the nitrogen balance in the two groups was similar [GH, -0.90 +/- 1.65 g/day (-64.2 +/- 117.8 mmol/day); saline, -1.08 +/- 0.95 g/day (-77.1 +/- 67.8 mmol/day); P = NS]. Mean plasma insulin-like growth factor I (IGF-I) concentrations rose from a basal value of 1.6 +/- 0.8 to 2.9 +/- 1.2 U/mL by 48 h after the first GH injection and ranged subsequently from 3.2 +/- 1.3 to 4.9 +/- 3.3 U/mL during GH injection (P less than 0.001). In contrast, the mean IGF-I concentration did not change in the group that received saline. Dietary restriction during the first week of study caused serum T3 concentrations to decline in both groups.(ABSTRACT TRUNCATED AT 400 WORDS)     

Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients

Lean body mass (LBM), fat mass (FM), and total bone mineral content are significantly reduced in adult GHD subjects who had received pediatric GH. To test the hypothesis that continued GH therapy after final height is necessary to attain adult body composition, we performed a prospective, multinational, randomized, controlled, 2-yr study in patients who completed pediatric GH treatment at final height. Patients were randomized to GH at 25.0 microg/kg x d (pediatric dose; n = 58) or 12.5 microg/kg x d (adult dose; n = 59) or no GH treatment (control; n = 32). LBM and FM were measured by dual energy x-ray absorptiometry and were centrally evaluated. IGF-I, IGF-binding protein-3, and lipid concentrations were also measured centrally. During the 2 yr, GH-treated patients gained a significant amount of LBM compared with controls (P < 0.001), but the change with the higher pediatric dose (14.2 +/- 11.7%) was not different from that seen with the lower adult dose (12.7 +/- 9.4%; P = 0.970). Similarly, the decrease in FM was significantly (P = 0.029) influenced by treatment, but with no dose effect (adult dose, -7.1 +/- 22.8%; pediatric dose, -6.0 +/- 26.6%; P = 0.950). When the GH treatment effect was analyzed by gender, males gained 15.6 +/- 9.8% and 14.3 +/- 11.7% LBM (P = 0.711) and lost 12.4 +/- 22.2% and 11.0 +/- 27.1% FM (P = 0.921) with the low and high doses, respectively. Females gained 8.3 +/- 7.3% and 12.5 +/- 12.8% LBM with the two doses (P = 0.630), but increased their FM by 3.5 +/- 16.2% with the lower dose and lost only 1.2 +/- 23.2% FM with the higher dose (P = 0.325). A similar pattern was seen in IGF-I sd score; the 2-yr GH dose response was significantly higher with the pediatric than with the adult dose in females (P = 0.008), but not males (P = 0.790). The divergent pattern of change in LBM and FM in males and females is consistent with normal developmental sexual dimorphism and indicates that GH-dependent progress to target body composition continues after the age at which GH treatment is usually terminated. Dose requirements may have to be adjusted by gender, with females requiring a higher dose than males.     

Safety and efficacy of growth hormone (GH) during extended treatment of adult Japanese patients with GH deficiency (GHD)

OBJECTIVES: To assess the effects of a growth hormone (GH) replacement therapy using a GH dose regimen based on serum insulin-like growth factor (IGF-I) concentrations in Japanese adults with GH deficiency (GHD). DESIGN: In this multicentre, uncontrolled, open-label study, Japanese adults with GHD who had received either GH replacement therapy (GH-GH group, n=35) or placebo (Placebo-GH group, n=36) in a previous randomised, double-blind, placebo-controlled trial were treated with GH replacement therapy for 48 weeks. GH treatment was started at a dose of 0.003 mg/kg/day administered by subcutaneous injection for the first 8 weeks, after which the dose was adjusted to maintain patients' serum IGF-I levels within the reference range adjusted for age and gender. Body composition, serum lipids, serum IGF-I and IGF binding protein-3 (IGFBP-3) levels were measured throughout study. Symptom and quality of life scores were also determined. RESULTS: Lean body mass (LBM) was increased compared with baseline (the end of the preceding double-blind trial) at 24 and 48 weeks, with a mean (+/-SD) increase of 1.3% (+/-4.2%) at week 48 in the GH-GH group (an increase of 6.6% [+/-6.0%] from the start of the preceding double-blind trial) and a larger increase of 4.7% (+/-5.9%) in the Placebo-GH group. Body fat mass (BFM) increased slightly from baseline in the GH-GH group with a mean increase of 2.9+/-10.6% at week 48 (a decrease from the start of the preceding double-blind trial at 48 weeks of 7.8% [+/-15.0%]) but decreased by 6.5% (+/-11.7%) at week 48 in the Placebo-GH group. Serum lipids were unchanged or slightly increased from baseline in the GH-GH group but patients' lipid profiles improved in the Placebo-GH group. In patients who received placebo during the double-blind study, individualised GH therapy in this open-label study increased mean LBM at 48 weeks by 6.2+/-6.8% in patients with CO GHD and by 3.0+/-4.4% in patients with AO GHD. Changes in mean LBM and mean BFM at week 48 were +4.1+/-4.5% and -2.4+/-10.5%, respectively, in females and +5.0+/-6.7% and -8.9+/-11.8%, respectively, in males. In patients who received GH treatment during the double-blind study, overall changes in LBM, BFM and IGF-I SD score after 24 weeks and 48 weeks were small, with no significant differences between subgroups. While the overall incidence of adverse events was broadly similar in the GH-GH and Placebo-GH groups (97% and 89%, respectively), the incidence of treatment-related events was higher in the GH-GH group (83% vs 42% in the Placebo-GH group). Most adverse events in both treatment groups were of mild or moderate severity and not clinically significant. The incidences of oedema and cases of high IGF-I during the IGF-I level-adjusted treatment regimen were lower than those during the preceding fixed dose titration. CONCLUSION: Long-term GH replacement therapy was well tolerated in Japanese adults with GHD. GH treatment maintained the improvements in body composition and lipid profiles in the patients previously treated in the double-blind study (GH-GH group) and improved these parameters in previously untreated patients (Placebo-GH group). Individualised GH administration based on IGF-I levels was well-tolerated and effective.     

Changing osteocalcin concentrations during pregnancy and lactation: implications for maternal mineral metabolism

We measured serum osteocalcin concentrations in 82 pregnant and 21 nonpregnant women. Osteocalcin values declined in the second trimester, but returned to nonpregnant levels late in the third trimester. The mean serum osteocalcin concentration in 36 women during pregnancy (mean gestation, 26 weeks) of 2.8 ng/mL was significantly lower than that in nonpregnant women (6.4 ng/mL; P less than 0.001) or term pregnant women at delivery (6.1 ng/mL; n = 46). Serum immunoreactive PTH (iPTH) levels were significantly higher during pregnancy than in nonpregnant women [97 +/- 5 vs. 56 +/- 4 ng/L (mean +/- SE); P less than 0.001]. No significant correlations were found between maternal osteocalcin concentrations and serum phosphorus, alkaline phosphatase, or iPTH, but significant negative correlations were found between osteocalcin and total calcium or total protein. Osteocalcin concentrations in midtrimester amniotic fluid were very low (mean, 0.3 +/- 0.1 ng/mL; n = 11). In 29 lactating mothers, the mean serum osteocalcin level was 9.5 +/- 1.5 ng/mL, significantly higher than in any of the other groups (P less than 0.05), but their serum calcium and iPTH levels were normal. There was no correlation between serum osteocalcin and calcium or iPTH concentrations in lactating women. These changes are compatible with a sequence in which bone turnover is reduced during early pregnancy, rebounds in the third trimester, and increases in postpartum lactating women.     

Insulin-like growth factor secretion by human B-lymphocytes: a comparison of cells from normal and pygmy subjects

Freshly isolated human B-lymphocytes from eight subjects and Epstein-Barr virus-transformed human B-lymphocytes from seven subjects were examined for their capacity to secrete insulin-like growth factor-I (IGF-I) and IGF-II and for their capacity to respond to human GH. Similar studies were conducted with Epstein-Barr virus-transformed lymphocytes collected from six African pygmies. When transformed B-lymphocytes from normal stature subjects were cultured for 3 weeks in RPMI-1640 medium (6 x 10(3) cells/75-cm2 flask at seeding), significant amounts of IGF-I, but no IGF-II, were produced. GH (150 ng/mL) significantly increased for control cells the amount of IGF-I produced at each sampling interval compared to that by unstimulated cultures (P less than 0.05 at 1 week; P = 0.005 at 3 weeks). At 3 weeks, cell counts of cultures compared were 4.13 +/- 0.39 X 10(6)/mL for unstimulated cells and 4.23 +/- 0.87 X 10(6)/mL for GH-stimulated cells. IGF-I production at this time interval by unstimulated cells was 2.8 +/- 2.3 ng/mL, and that by GH-stimulated cells was 12.3 +/- 2.5 ng/mL (P = 0.005). Cell multiplication rates of control cultures were increased in 1 week by GH stimulation [GH stimulated, [16.7 +/- 22.0 X 10(4) cells, unstimulated, 5.73 +/- 4.1 X 10(4) cells; (mean +/- SD); n = 14; P less than 0.01]. Similar results occurred with GH studied at a lower concentration of 10 ng/mL for 3 weeks. Freshly isolated B-lymphocytes did not secrete IGF-I and II after 5 days of culture with GH. Cultures established from cells derived from pygmies produced significantly less IGF-I (4.24 +/- 2.62 ng/mL) when stimulated with 150 ng/mL GH than cultures of cells from normal stature subjects (12.3 +/- 2.5 ng/mL; 0.005 less than P less than 0.01). The cultures compared had a similar cell density. A similar significant difference in IGF-I secretion occurred between cultures of pygmy and control cells stimulated with 10 ng/mL GH. These data are consistent with previous in vivo studies in which pygmies failed to increase IGF-I and exhibit metabolic responses to exogenous GH.     

Ghrelin and its relationship to growth hormones during normal pregnancy

OBJECTIVE: Ghrelin and GH secretagogue receptors have been found in reproductive organs, including the placenta. The physiology of ghrelin in pregnancy has not been explored. In human pregnancy, pituitary GH is gradually replaced by placental GH (PGH). The present study was undertaken to examine serum ghrelin levels during normal pregnancy and to determine to what extent changes in ghrelin levels coincide with changes in serum levels of free and total GH and PGH. Design Prospective study with blood sampling from pregnant women in gestational weeks 8, 18, 26 and 36 and postpartum. PATIENTS: Eleven nondiabetic pregnant women with singleton pregnancies. MEASUREMENTS: Serum ghrelin was determined using an in-house radioimmunoassay. Serum PGH was determined in a solid-phase immunoradiometric assay, serum GH and insulin in a time-resolved immunofluorometric assay, and serum GHBP in an in-house immunofunctional assay. RESULTS: Serum ghrelin levels peaked in week 18 (1.20 +/- 0.09 microg/l) and the lowest levels were observed in late third trimester (0.87 +/- 0.06 microg/l), corresponding to a mean decrease of 27.7% (P < 0.001) from peak levels. An increase was observed again postpartum. Serum GH diminished throughout pregnancy to low third-trimester values (0.12 +/- 0.03 microg/l; P < 0.001), and PGH increased to 25.7 +/- 2.86 microg/l (P < 0.001) in week 36. Neither total nor calculated free levels of growth hormones correlated to ghrelin levels, and no significant correlations were observed between ghrelin and maternal body mass index (BMI) or fasting insulin levels. CONCLUSIONS: Serum ghrelin levels peak around mid-gestation in human pregnancy. Ghrelin levels during pregnancy are at their lowest in the third trimester at a time of increased body weight, development of insulin resistance and high serum levels of PGH. However, no associations were observed between ghrelin and the two growth hormones.     

Timing of onset of growth hormone deficiency is a major influence on insulin-like growth factor I status in adult life

OBJECTIVE: Several reports have suggested that IGF-I levels in patients with childhood-onset (CO) GH deficiency are lower than those observed in patients with adult-onset (AO) GH deficiency. However, these reports are unsatisfactory as there are several differences between the cohorts studied other than the timing of onset of GH deficiency; in particular, the patients were not matched for equal severity of GH deficiency. We have pursued this question further by examining the IGF-I standard deviation score (SDS) in patients with CO and AO GH deficiency, with equal degrees of severity of GH deficiency, as defined by the peak GH response to the insulin tolerance test (ITT). PATIENTS AND MEASUREMENTS: IGF-I SDS were compared in 146 non acromegalic patients (69 male), aged 15.7-76.6 years (median 33.4 years), bone mass index (BMI) 27.8 +/- 5.8 kg/m2, with severe GH deficiency (peak GH response < 9 mU/l to insulin-induced hypoglycaemia). Patients were subdivided by timing of onset of GH deficiency and the peak GH response to the ITT (GH response < or = 1 mU/l, group 1; > 1-3 mU/l, group 2; > 3-6 mU/l, group 3; > 6-8.9 mU/l, group 4). RESULTS: The IGF-I SDS (mean value +/- SD) in the CO group (n = 63) as a whole was significantly lower than that found in the AO group (n = 83) (-3.7 +/- 2.8 vs.-1.55 +/- 2.2, respectively; P < 0.0001). Despite this, there was no significant difference in the peak GH response to an ITT between the two cohorts (2.8 +/- 2.3 mU/l in the AO cohort and 2.6 +/- 2.2 mU/l in the CO cohort; P = 0.5). When the cohorts were subdivided by severity of GH deficiency, there remained a significant difference in IGF-I SDS in groups 1 (P < 0.0001), 2 (P = 0.05) and 3 (P < 0.05), but there was no significant difference between the AO and CO cohorts in group 4. The peak GH response to an ITT was similar in the AO and CO cohorts in all groups (P = 0.8, 0.8, 0.9 and 0.3 in groups 1-4, respectively). Although increasing severity of hypopituitarism was associated with a decline in IGF-I SDS in the CO cohort (P < 0.01), this was not the case in the AO cohort (P = 0.3). CONCLUSION: These data support the hypothesis that there is an innate difference between adult patients with either CO or AO GH deficiency that cannot be explained solely by variation in the severity of GH deficiency. A possible explanation is that childhood GH deficiency programmes the subsequent relationship between GH and IGF-I in adult life or that the body composition changes, which are more severe in AO GH deficiency, influence IGF-I status.     

The severity of chronic heart failure due to coronary artery disease predicts the endocrine effects of short-term growth hormone administration

Treatment with human recombinant GH has yielded conflicting results in patients with heart failure. As GH sensitivity may be important for treatment effects, the present study evaluated GH secretion and sensitivity in noncachectic patients with ischemic heart failure. Twenty clinically stable, male patients with moderate heart failure (mean New York Heart Association class, 2.0 +/- 0.8; mean ejection fraction, 30.0 +/- 8.4%) due to coronary artery disease were randomly assigned single blind to a low dose (group A; n = 10) and a high dose (group B; n = 10) group, receiving either 5 microg/kg x day recombinant human GH for 4 days followed by 10 microg/kg x day GH for another 4 days or 10 and 20 microg/kg x day GH, respectively. Cardiac function was assessed by echocardiography. Serum insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and 24-h urinary GH excretion as a measure of pituitary GH secretion were determined at baseline and on days 5 and 9. Baseline IGF-I and IGFBP-3 levels and GH excretion were significantly diminished compared to those in age-matched controls. There was a dose-dependent increase in IGF-I and IGFBP-3 during GH treatment. The increase in IGF-I induced by 10 microg/kg x day GH correlated positively to left ventricular ejection fraction (r = 0.59; P = 0.006) and inversely to left ventricular end-diastolic and end-systolic dimensions (r < -0.6 and P < 0.01 for both). In conclusion, GH secretion and serum levels of IGF-I and IGFBP-3 are diminished in patients with moderate ischemic heart failure. Left ventricular function determines the sensitivity of the GH/IGF-I system, measured as the IGF-I response to GH application. This finding suggests that individual dose adjustments may be an indispensable prerequisite for successful GH therapy in heart failure.     

Placental growth hormone (GH), GH-binding protein, and insulin-like growth factor axis in normal, growth-retarded, and diabetic pregnancies: correlations with fetal growth

We previously described significant changes in GH-binding protein (GHBP) in pathological human pregnancy. There was a substantial elevation of GHBP in cases ofnoninsulin-dependent diabetes mellitus and a reduction in insulin-dependent diabetes mellitus. GHBP has the potential to modulate the proportion of free placental GH (PGH) and hence the impact on the maternal GH/insulin-like growth factor I (IGF-I) axis, fetal growth, and maternal glycemic status. The present study was undertaken to investigate the relationship among glycemia, GHBP, and PGH during pregnancy and to assess the impact of GHBP on the concentration of free PGH. We have extended the analysis of specimens to include measurements of GHBP, PGH, IGF-I, IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 and have related these to maternal characteristics, fetal growth, and glycemia. The simultaneous measurement of GHBP and PGH has for the first time allowed calculation of the free component of PGH and correlation of the free component to indexes of fetal growth and other endocrine markers. PGH, free PGH, IGF-I, and IGF-II were substantially decreased in IUGR at 28-30 weeks gestation (K28) and 36-38 weeks gestation (K36). The mean concentration (+/-SEM) of total PGH increased significantly from K28 to K36 (30.0 +/- 2.2 to 50.7 +/- 6.2 ng/mL; n = 40), as did the concentration of free PGH (23.4 +/- 2.3 to 43.7 +/- 6.0 ng/mL; n = 38). The mean percentage of free PGH was significantly less in IUGR than in normal subjects (67% vs. 79%; P < 0.01). Macrosomia was associated with an increase in these parameters that did not reach statistical significance. Multiple regression analysis revealed that PGH/IGF-I and IGFBP-3 account for 40% of the variance in birth weight. IGFBP-3 showed a significant correlation with IGF-I, IGF-II, and free and total PGH at K28 and K36. Noninsulin-dependent diabetes mellitus patients had a lower mean percentage of free PGH (65%; P < 0.01), and insulin-dependent diabetics had a higher mean percentage of free PGH (87%; P < 0.01) than normal subjects. Mean postprandial glucose at K28 correlated positively with PGH and free PGH (consistent with the hyperglycemic action of GH). GHBP correlated negatively with both postprandial and fasting glucose. Although GHBP correlated negatively with PGH (r = -0.52; P < .001), free PGH and total PGH correlated very closely (r = 0.98). The results are consistent with an inhibitory function for GHBP in vivo and support a critical role for placental GH and IGF-I in driving normal fetal growth.