High-dose Growth Hormone Research Articles

Growth-Promoting and Psychological Effects of High-Dose Growth Hormone Treatment in Children with Intrauterine Growth Retardation.

Growth-Promoting and Psychological Effects of High-Dose Growth Hormone Treatment in Children with Intrauterine Growth Retardation.

Early, Discontinuous, High Dose Growth Hormone Treatment to Normalize Height and Weight of Short Children Born Small for Gestational Age: Results Over 6 Years

Early, Discontinuous, High Dose Growth Hormone Treatment to Normalize Height and Weight of Short Children Born Small for Gestational Age: Results Over 6 Years

Early, Discontinuous, High Dose Growth Hormone Treatment to Normalize Height and Weight of Short Children Born Small for Gestational Age: Results Over 6 Years

Most children born small for gestational age (SGA) normalize their size through spontaneous catch-up growth within the first 2 yr after birth. Some SGA children fail to do so and maintain an abnormally short stature throughout childhood. We have previously reported that high dose GH treatment (66 or 100 microg/kg x day s.c. over 2 yr; age at start, 2-8 yr; n = 38) induces pronounced catch-up growth in short children born SGA, thereby normalizing their height and weight in childhood. Here, we report on the further prepubertal growth course of these children over the first 4 yr after withdrawal of early, high dose GH treatment. Of the 38 treated children, none developed precocious puberty, and 22 remained prepubertal. Mean age of the latter at start of GH was 4.4 yr, height was -3.7 SD score, and height after adjustment for midparental height was -2.9 SD score. Height increased by an average of 2.5 SD during the 2 yr of GH treatment and decreased by 0.4 and 0.3 SD, respectively, during the first and second year after GH withdrawal. Subsequently, when stature was not extremely short at the start (mean adjusted height SD score, -2.7; n = 13), no further GH treatment was given, and the adjusted height was stabilized around -1.0 SD score; when stature was very short at the start (mean adjusted height, -3.3 SD score; n = 9), a second course of GH treatment (66 microg/kg x day s.c.) was initiated either 2 yr (n = 5) or 3 yr (n = 4) after initial GH withdrawal. This second course was associated with renewed catch-up growth and also resulted in a mean adjusted height of -1.0 SD score. In each subgroup, the pattern of the weight course paralleled that of the height course; GH treatment was well tolerated. In conclusion, early, discontinuous, high dose GH treatment appears to be a safe and efficient option to normalize prepubertal height and weight in the majority of short SGA children. It remains to be examined whether the normalized stature will be maintained during pubertal development, either with or without further GH treatment.

Response to growth hormone therapy in experimental ischemic acute renal failure

In acute renal failure (ARF), the gene and peptide expression of insulin-like growth factor-I (IGF-I) falls. Because IGF-I is regulated by growth hormone (GH) and because kidney GH receptor expression is also attenuated in ARF, the impaired IGF-I expression may partly reflect local GH resistance. Because IGF-I treatment accelerates recovery from ARF, we determined whether high-dose GH therapy could overcome this putative GH resistance, stimulate IGF-I production, and enhance recovery. Rats with ARF were given 2.5 mg GH or vehicle (V) over 2 days, beginning 24 hours before the onset of ARF. GH prevented weight loss but did not modify the course of ARF. Next we determined whether the failure of GH to modify kidney recovery could reflect a failure to stimulate renal IGF-I gene expression. Rats were treated with GH or V over an 18-hour period beginning 1 day after the induction of ARF. Hepatic IGF-I mRNA and serum IGF-I peptide levels rose significantly with GH treatment, but the low kidney IGF-I mRNA levels did not respond. We conclude that the failure of GH to enhance recovery from ARF is caused by impaired GH-stimulated renal IGF-I production, while the maintenance of body weight likely reflects the systemic effects of the increase in hepatic IGF-I production.

Pharmacokinetics and metabolic effects of high-dose growth hormone administration in healthy adult men.

To evaluate pharmacokinetics of growth hormone (GH) and its effects on IGF-I, glucose, insulin, nonesterified fatty acid (NEFA) and triglyceride (TG), fifteen Japanese healthy adult male volunteers (20-27 years old) were studied. The subjects were divided into three groups, and received with a single s.c. injection of 0.075, 0.15 and 0.30 IU/kg of GH, respectively. The subjects assigned to receive 0.30 IU/kg were administered for additional 6 days. After a single administration of GH, Cmax and AUC of GH were increased in a dose-dependent manner. There was a significant positive correlation between the AUC and the T1/2 (r=0.516, P<0.05). Total body clearance was significantly greater in 0.075 IU/kg group than the other groups and showed a significant negative correlation with Cmax (r=-0.694, P<0.005) and AUC (r=-0.723, P<0.005). After a single administration of each dose, serum IGF-I concentrations were increased gradually. In the repeated administered group (0.30 IU/kg), IGF-I concentrations almost reached a plateau at a significantly high level four days after the start of administration and remained at a high level (786-405.4 ng/ml) until day 8. There was no significant difference in diurnal change of blood glucose and serum insulin after a single administration of GH among three groups. In the 0.3 U/kg group, there was no significant difference in diurnal change of blood glucose between day 1 and day 7, but serum insulin level was significantly higher in day 7 than in day 1 (P<0.01). Serum concentrations of NEFA were increased over time after administration in all subjects administered once or repeatedly. TG concentrations showed no changes after single administration of each dose level, but were significantly increased on day 7 in the subjects repeatedly treated with 0.30 IU/kg/day. This effect is speculated to be caused by high dose GH treatment. The above findings demonstrated that higher GH dose significantly influences on carbohydrate and lipid metabolism. It remains necessary to elucidate what kinds of effects of the long-lasting increased levels of insulin and triglyceride, even if reversible, would have on glucose and lipid metabolism.

Monoclonal antibody enhanced stimulation of human growth hormone action in vitro using ovine costal cartilage growth plate chondrocytes.

Investigations into the mechanism underlying antibody-mediated enhancement of growth hormone action have been hampered by the lack of an in vitro assay system. In this work, we have used isolated ovine costal cartilage growth plate chondrocytes to demonstrate, for the first time, that monoclonal antibody EB1 can enhance the proliferative actions of human growth hormone on this cell type. Chondrocytes were cultured for 14 days prior to exposure to GH+/-monoclonal antibody EB1 for a 4-day treatment period. Human growth hormone alone promoted a significant dose-dependent increase in chondrocyte proliferation; maximal stimulation was achieved at about 3.3-10 ng/ml growth hormone, and at higher doses of growth hormone, the response declined. Monoclonal antibody EB1 was shown to enhance the proliferative activity of 10 ng/ml human growth hormone in a significant dose dependent fashion. In conclusion, our results demonstrate that an antibody capable of enhancing GH activity in vivo also has the capacity to potentiate GH activity in vitro. This system may provide an important tool for investigations into the mechanism of GH action, and how this is modified by GH enhancing MAbs.

Birth weight influences the initial response to growth hormone treatment in growth hormone-insufficient children.

To determine the influence of birth weight on the first year response to growth hormone (GH) replacement in children with isolated GH insufficiency. A longitudinal study of response to daily GH treatment (15-26 IU/m2/week) was performed in 16 singleton Caucasian prepubertal children (11 boys, 5 girls) with isolated GH insufficiency (peak GH response to insulin tolerance test <13.5 mU/L) attending a pediatric endocrinology clinic. Change in height velocity standard deviation scores, during the 6 to 12 months before starting GH and the 12 months after, were used to reflect responsivity to GH treatment. Potential influencing variables considered by regression analysis were birth weight standard deviation score (BWSDS), peak GH response to insulin tolerance testing, midparental height standard deviation score, age at treatment, and dose of GH administered. Mean BWSDS was -0.51 (SD, 1.0). Change in height velocity standard deviation score was correlated positively with BWSDS (r = 0.64) and negatively with peak GH (r = -0.59). Stepwise linear regression analysis confirmed the influence of BWSDS on response to GH treatment. The continuum of birth weight influences initial responsivity to GH treatment in GH-insufficient children. This may reflect relative insensitivity in the growth hormone or insulin-like growth factor axis. The influence of birth weight on final height and benefit of using higher doses of GH in these children remains to be seen.

Short stature of prenatal origin: craniofacial growth and dental maturation.

Recently, children born small for gestational age (SGA) with a catch-up growth failure, have been selected for high dose growth hormone (GH) treatment. In order to gain greater insight concerning dentofacial growth and maturation of these patients, and to evaluate the possible effects of high does GH administration on facial structures, craniofacial growth and dental maturation were evaluated in short SGA persons. Seventy-seven cephalograms and orthopantomograms were available from 48 subjects, aged between 2 and 32 years. Craniofacial growth was assessed by calculating age- and gender-specific standard deviation scores (SDS) for eight linear and five angular measurements. Tooth formation was evaluated by means of a dental delay score (i.e. dental age minus chronological age). The SDS for craniofacial growth measurements for the lateral aspect showed a short anterior cranial base (-1.8 SDS), a small retropositioned mandible (< or = -1.7 SDS) and a small maxilla (-1.5 SDS); a high mandibular plane angle (+1.9 SDS) and a wide cranial base angle (+1 SDS). These findings result in a small retrognathic face with a relatively increased lower anterior face height (+1.7 SDS). In contrast to skeletal maturation, dental age was not delayed. The general growth retardation is, apparently, reflected to a differential extent within the craniofacial complex, while dental maturation appears to be a distinct process tightly linked to chronological age, and independent of general growth and bone age.

Treatment of severe short bowel syndrome with high dose growth hormone and glutamine

Treatment of severe short bowel syndrome with high dose growth hormone and glutamine

Growth hormone treatment of short children born small for gestational age: reappraisal of the rate of bone maturation over 2 years and metanalysis of height gain over 4 years

A minority of children born small for gestational age (SGA) fail to achieve sufficient catch-up growth during infancy and remain short throughout childhood, apparently without being growth hormone (GH) deficient. A previous metanalysis of four trials revealed that GH treatment over a period of 2 years induced a dose-dependent acceleration of linear growth and, to a lesser extent, of the rate of bone maturation in short, prepubertal children born SGA. The rate of bone maturation and the change in height SDS for bone age from the previous 2-year metanalysis have been re-analysed according to chronological age (two prepubertal age groups: group A, 3.0-5.9 years old; group B, 6.0-8.9 years old). The rate of bone maturation was slower in younger than in older prepubertal children; this difference was more marked in children receiving high-dose (0.2 or 0.3 IU/kg/day) GH treatment (p < or = 0.01). Accordingly, the change in height SDS for bone age was increased by high-dose GH treatment in both age groups (p < or = 0.01), and was more pronounced in younger than in older children (1.45 +/- 0.28 versus 0.63 +/- 0.20; p < or = 0.01). Height SDS data from 100 short, prepubertal children born SGA have been analysed over 4 years. The change in height SDS appeared to be related to the average dose of GH. A mean GH dose of 0.1 IU/kg/day over 4 years was administered either as 0.1 IU/kg/day for 4 years (continuous) or as 0.2 IU/kg/day for 2 years, followed by 2 years without GH treatment (discontinuous). After 4 years of treatment, the increase in height SDS for the continuous and discontinuous treatment schedules was similar, being 1.42 +/- 0.10 SDS and 1.58 +/- 0.17 SDS, respectively. In a second regimen, a mean GH dose of 0.2 IU/kg/day over 3 years was administered either as 0.2 IU/kg/day for 3 years (continuous) or as 0.3 IU/kg/day for 2 years, followed by 1 year without GH treatment (discontinuous). After 3 years, the increase in height SDS with the continuous and discontinuous treatment schedules was similar, being 2.01 +/- 0.18 SDS and 2.22 +/- 0.16 SDS, respectively. GH administration was well tolerated in all treatment groups. In conclusion, the rate of bone maturation in short, prepubertal children born SGA treated with GH appeared to depend not only on the dose of GH, but also on the age of the child. GH treatment resulted in a prolonged increase in height SDS, the magnitude of the rise being dependent on the average GH dose rather than on the continuous or discontinuous mode of GH administration.

Expectation bias with respect to growth hormone therapy in Turner syndrome.

More than 10 years ago, preliminary reports indicated that high-dose growth hormone therapy was beneficial in treating short stature in girls with Turner syndrome (1, 2). In previous reports, with lower doses of growth hormone and suboptimal therapeutic regimens i.e. three times weekly vs daily, and intramuscular vs subcutaneous injection, no growth promoting effect was demonstrated (3, 4). Until recently, the positive effects of growth hormone therapy were documented by increased growth velocities, improved height predictions and/or a gain in actual height, when height during therapy was compared with ‘projected height’ using Turner syndrome specific growth charts (5, 6). The positive results were viewed with cautious optimism. It was generally stated that further studies were needed to document the effects of different therapeutic regimens on bone maturation, long-term growth and final height. In several studies bone age advanced significantly more than chronological age during high-dose growth hormone therapy alone or in combination with oxandrolone or estrogens (7–9). Bone age accelerates especially at younger ages, so it is suggested that the optimal age of starting growth promoting therapies is 9 years (7). This recommendation contradicts the general observation in patients with ‘classical’ growth hormone deficiency, that an earlier start of therapy significantly improves adult height. Today, results on long-term growth and adult height are available. The results vary from study to study indicating major improvements in adult height and overt psychosocial benefit in some (9–11) or minor, insignificant height gains and little changes in the psychosocial status in other clinical trials (12, 13). It is a major disadvantage of all published studies that changes in growth velocity and adult height have been compared with historical controls only, thus not accounting for a possible normal acceleration of growth in untreated Turner syndrome patients. The presently available data are encouraging, though still controversial. Optimism still prevails and will hopefully be substantiated after all ongoing clinical trials, including the data from the two randomized clinical trials initiated in Canada (14) and the US (15), have published their final results. In addition, it is necessary to establish whether a psychosocial benefit is obtained during, at the end of, and years after therapy with or without a documented effect of growth hormone therapy on adult height. A bias in favor of the publication of positive and statistically significant results is well documented in clinical medicine (16). It should be avoided by reporting the results of all ongoing trials with growth promoting therapies in Turner syndrome. This is especially important, since concerns have been raised about bias in industry-supported clinical research, about data presented in the absence of peer review (14) and the pressure in favor of treatment exerted by parental groups. Many questions still remain, so that additional prospective and randomized clinical trials with psychosocial guidance are required to evaluate, for example, bone age development in patients and controls, to document a possible normal acceleration of growth in untreated patients, and to determine final height in treatment and control groups (17). The major determinant of randomized clinical trials is the assessment of the psychosocial well-being in treated and untreated girls with Turner syndrome. The effects should be assessed during therapy and at the time when adult height is reached. Furthermore, long-term evaluations should be performed several years after therapy, when the enthusiasm and positive reinforcement of the therapeutic intervention by physicians and parents have waned. It will be necessary to assess the importance of a ‘minor’ or ‘major’ increase in adult height during the routine of everyday adult life and with the knowledge that adult stature for many patients is still far from being ‘normal’. In the coming years we, hopefully, will be able to justify the long and expensive treatments whose potential long-term risks still remain uncertain. More than 10 years ago, large clinical trials of growth hormone therapy were started in girls with Turner syndrome. Hopefully it will not take another 10 years until randomized, prospective and controlled clinical trials are initiated to find the necessary answers to the many remaining questions.

Effects of estrogen and growth hormone on skeleton in the ovariectomized rat with hypophysectomy.

To investigate whether growth hormone (GH) and 17beta-estradiol (E2) replacement can prevent osteopenia induced by pituitary and ovarian hormone deficiency [by hypophysectomy and ovariectomy (HX+OV)], we administered relatively low doses of GH (2.3 IU x kg(-1) x day(-1)) and E2 (100 microg x kg(-1) x wk(-1)) in experiment 1 and relatively high doses of GH (13.5 IU x kg(-1) x day(-1)) and E2 (3,500 microg x kg(-1) x wk(-1)) in experiment 2 to 2-mo-old HX+OV Sprague-Dawley rats for 6 wk. Our data show that the HX+OV of rats results in diminished periosteal bone formation, longitudinal bone growth, and decreased cancellous bone volume. Administration of either the low or high dose of GH to these rats increased their systemic growth, serum levels of osteocalcin, and cortical bone formation. Either low or high doses of GH or E2 alone only partially prevent cancellous bone loss. However, the combined treatment of GH plus E2 resulted in an additive increase in the cancellous bone mass. We conclude that the additive effect of GH plus E2 on cancellous bone is attributed to the suppressive effect of E2 on bone resorption and the anabolic effect of GH on bone formation.

Insulin-like growth factor-I liposomal gene transfer and systemic growth hormone stimulate wound healing.

Many of the anabolic effects of growth hormone (GH) act through insulin-like growth factor-I (IGF-I). Systemic administration of GH in combination with IGF-I has been shown to stimulate wound reepithelialization, however, it causes hyperglycemia or hypoglycemia, respectively. We hypothesize that very low doses of IGF-I in a liposome form will have the same positive wound-healing effect when administered locally as the higher doses of GH plus IGF-I given systemically. To test this hypothesis, rats were given a 40% TBSA full-thickness scald injury and received either placebo IGF-I (5.0 mg/kg/day, subcutaneously), IGF-I liposome (0.9 microgram/kg/week, subcutaneously), or a combination of GH and IGF-I, or IGF-I liposomes for 8 weeks. GH in combination with IGF-I showed a significant increase in postburn weight. Wound reepithelialization, measured by computerized planimetry as percentage original wound area, was significantly increased in rats receiving GH plus IGF-I, GH plus IGF-I liposomes, and IGF-I liposomes when compared to sham, or IGF-I (p < 0.05). Results indicate that small doses of IGF-I, delivered in the form of liposomes, are equally effective in increasing burn wound reepithelialization as the higher doses of GH plus IGF-I, or GH plus IGF-I liposomes.

Growth performance and respiratory burst activity in rainbow trout treated with growth hormone and vaccine

Size-selected (167±11mm) female rainbow trout were: given a high (1·8μgg−1body weight per week) or low (0·35μgg−1) dose of recombinant bovine growth hormone (GH), delivered by cholesterol pellet implant; injected with a commercial bivalent (vibriosis–furunculosis) vaccine; provided with each dose of GH plus vaccine; implanted with a pellet alone; or left untreated (N=20 per group). Growth in each treatment group was monitored over a 7 week period. Four weeks into the trial, and at trial termination, head kidney neutrophils were quantified using a histochemical method, and their respiratory burst (CL) response evaluated (N=10 per group). By week 4 of the trial, high dose GH treatment was observed to enhance the CL response of vaccinated fish (P<0·05) above that of control and other groups. High dose GH treated animals also returned greater, although relative to week 4 data significantly lower, CL response at trial termination. Vaccination had an overall negative effect (P<0·05) upon trout growth performance during the trial, although this consequence was annulled when vaccine was co-administered with high dose GH. When considered conjointly with the findings of others, the results of the present investigation provide evidence in support of the existence of a hypothalamo-pituitary-immune axis in teleosts.

Growth Promotion and Turner-Specific Bone Age after Therapy with Growth Hormone and in Combination with Oxandrolone: When Should Therapy Be Started in Turner Syndrome?

The aims of this comparative multicenter study of 67 girls with Turner syndrome (TS) on three different therapeutical regimens were, first, to evaluate the effect of either recombinant human growth hormone (GH) alone or in combination with the anabolic steroid oxandrolone (Oxa) on height velocity and on Turner-specific bone age (BA'TS) and, second, to estimate the gain in final height taking the age at the onset of treatment into account. The mean advancement of BA'TS in 2 years of treatment was 2.5 years/2 years in group 1 (low dose GH: 16 IU/m2/week), 2.8 years/2 years in group 2 (high dose GH: 28 IU/m2/week) and 3.3 years/2 years in group 3 (GH: 24 IU/m2/week + Oxa: 0.06 mg/kg/day) instead of the expected 2 years/2 years advancement in untreated girls with TS. On all treatment regimens the advancement of BA'TS was more pronounced in the younger girls. In many girls with a BA'TS below 9 years at the onset of treatment the increase in height did not outweigh the advancement in BA'TS, suggesting that starting growth-promoting treatment before 9 years would not be the best way to improve final height. In our opinion, the optimal age for starting growth-promoting therapy is at 9 years. A start at a younger age might have no advantage in regard of an ultimate gain in final height. On the other hand, therapy should not be delayed much after the age of 9 years giving the girls with TS the possibility to catch up substantially before estrogen treatment is initiated.

Exogenously administered growth hormone and insulin-like growth factor-I alter intracellular Ca2+ handling and enhance cardiac performance. In vitro evaluation in the isolated isovolumic buffer-perfused rat heart.

It has been proposed that chronic treatment with growth hormone (GH) or insulin-like growth factor-I (IGF-I) in the rat may enhance cardiac function in vivo. To confirm these findings and elucidate the mechanisms by which cardiac function is modulated, we studied isolated buffer-perfused rat hearts after 4 weeks of treatment with high doses of GH and IGF-I alone or in combination. Mechanical parameters were measured at 50% of the intracardiac balloon volume at which maximal developed pressure (DevP) occurred. EC50 of the force-Ca2+ relationship and maximal Ca(2+)-activated systolic wall stress (max sigma s) were assessed by increasing Ca2+ in the perfusate in a stepwise fashion and plotting systolic wall stress (sigma s) versus intracellular peak systolic Ca2+, measured by the aequorin bioluminescence method. We found a marked increase of systolic pressure (Ps), DevP, and (+dP/dt)/DevP in the treated groups compared with the control group. The combination group showed a blunted effect. sigma s was increased in all treated groups for a perfusate Ca2+ concentration of > 1.5 mmol/L. The enhanced systolic performance can be explained by an increase of the overall Ca2+ responsiveness due to an increased maximal response to Ca2+ even though the EC50 of the Ca(2+)-dose response was also slightly increased. Ps was further enhanced by an increase of the relative wall thickness induced by the treatment. Diastolic pressure, diastolic Ca2+, and the amplitude and time course of the Ca2+ transient were not influenced by any treatment protocol. All treatments caused increases of body and heart weight. These data support the hypothesis that both IGF-I and GH directly affect cardiac performance by altering cardiac geometry as well as by enhancing max sigma s.

Evaluation of clinical and laboratory parameters during 2 years of growth hormone treatment in prepubertal children with chronic renal failure.

Twelve prepubertal children with chronic renal failure (CRF) were treated with human growth hormone (GH) (1.2 IU/kg/week) for 2 years. High doses of GH clearly increased growth velocity, from 3.8 +/- 1.3 to 9.6 +/- 1.5 (P = 0.0001) and 6.9 +/0 0.8 cm/year (P = 0.0001) after the 1st and 2nd year of treatment, respectively, leading to a mean height gain of 1.4 SD. During the 1st year of treatment the height increment, expressed in SDS, correlated negatively with chronological age (P = 0.003). Basal insulin-like growth factor 1 (IGF 1) levels were normal or elevated (7/12 patients) and correlated positively with the overnight integrated GH concentration (r = 0.68, P < 0.001). Basal insulin-like growth factor binding protein 3 (IGF-BP3) levels were elevated in 8/12 patients. GH induced a significant increase in IGF 1 and IGF-BP3 levels; IGF 1 peaked after 6 months (when growth velocity was optimal) and IGF-BP3 peaked after 12 months. The mean glomerula filtration rate, measured by inulin clearance and corrected for body surface area, fell after the 1st year of treatment, and significantly so at the end of the 2nd year (P = 0.02). Early initiation of GH therapy during CRF may prevent severe growth retardation and allow these children to attain normal height before dialysis and transplantation.

High-dose growth hormone treatment of short children born small for gestational age

High-dose growth hormone treatment of short children born small for gestational age

Growth hormone normalizes vertebral strength in ovariectomized rats

Ten-month-old lactating breeders were ovariectomized and kept on a low calcium diet. One month after ovariectomy, the rats were dosed once daily for 6 months with either a low dose of growth hormone (GH) (0.05 mg), a high dose of GH (1 mg), estrogen plus gestagen (E-G) [17 beta-estradiol (0.1 mg); norethisterone-acetate (0.05 mg)], or a combination of GH and E-G. Mechanical competence, apparent dry density, apparent ash density and ash concentration were measured in the fourth lumbar vertebral body. The reduced mechanical strength, ash density and ash concentration found in the vertebral body of ovariectomized animals were prevented by the high dose of GH alone, or in combination with E-G. E-G alone partly prevented the decline in ash density and ash concentration, but did not affect the reduced mechanical strength seen after ovariectomy. Only minor effects were observed after treatment with the low dose of GH, alone or in combination with E-G. In conclusion this study shows that GH administration prevents the decline in mechanical strength and bone mineral density seen in rats after ovariectomy.

Growth hormone and insulinlike growth factor I enhance host defense in a murine sepsis model.

To investigate the effects of exogenous growth hormone (GH) and insulinlike growth factor I (IGF-I) on host defense and survival in a murine model of Escherichia coli sepsis. Prospective randomized experimental trials. Laboratory. Nine-week-old female BALB/c mice. Mice were injected subcutaneously with 4.8 or 0.48 mg/kg of body weight per day of GH, 24 or 2.4 mg/kg of body weight per day of IGF-I or, as a control, normal saline solution, for 6 days. Mice were then challenged intraperitoneally with 1 x 10(8) colony-forming units per body of E coli. Fifty mice were observed for survival. In the next experiments, samples from the high-dose GH, high-dose IGF-I, and saline control groups were harvested before or at 4 or 6 hours after challenge. Numbers of peritoneal exudative cells and tissue-viable bacterial counts were determined. Peritoneal exudative cells were cultured with lipopolysaccharide (10 micrograms/mL) for 24 hours. Levels of tumor necrosis factor, interleukin-1, and interleukin-6 in the peritoneal lavage fluid, plasma and supernatants of peritoneal exudative cell culture were measured. Both high and low doses of GH and high-dose IGF-I significantly prolonged survival. Growth hormone and IGF-I significantly increased peritoneal exudative cell numbers and reduced viable bacterial counts in the peritoneal lavage fluid and the liver. These hormones significantly suppressed excessive systemic cytokine production, while enhancing in vitro cytokine production and preserving local cytokine responses. The immunomodulation produced by administration of GH or IGF-I leads to improved host defense in this murine model of E coli sepsis.