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R Brauner

Publications and source records attributed to R Brauner.

At least 37 records · Page 2Linked to original sources
PubMed1997

Intracoronary adenovirus-mediated transfer of immunosuppressive cytokine genes prolongs allograft survival.

BACKGROUND: Intracoronary transfer and expression of recombinant genes in the intact heart is now feasible. In the transplant setting, local modulation of host immune responses by a genetically modified allograft may offer an attractive alternative to systemic immunosuppression. METHODS: We tested the efficacy and in vivo effect of intracoronary transfer of two immunosuppressive cytokine genes. First-generation E1-deleted adenoviral vectors expressing the Epstein-Barr virus interleukin-10 (AdSvIL10) or human transforming growth factor--beta 1 (AdCMVTGF-beta) were used. Rabbit cardiac allografts were transduced during cold preservation by slow (1 ml/min) intracoronary infusion of 10(10) pfu/gm diluted viral vectors and then implanted heterotopically. Controls included E1-deleted adenovirus (Ad5dI434) and AdCMVLacZ. Beating allografts were collected on day 4 for analysis of gene transfer efficacy and distribution. Additional grafts were used for evaluation of alloreactivity (n = 34). RESULTS: Mean allograft viral uptake was 81% (up to 91%). Polymerase chain reactions and reverse transcription-polymerase chain reactions confirmed the presence and expression of both genes in the grafts. beta-Galactosidase staining in AdCMVLacZ-infected grafts demonstrated efficient gene expression, which was highest (100%) in subepicardial regions. More homogeneous transmyocardial distribution of the transgene (in 25% to 40% of cells) could be achieved by pulsatile slow delivery. Allograft survival was 6.9 +/- 0.9 days in controls (n = 12), 11.1 +/- 1.7 days in AdCMVTGF-beta-infected grafts (n = 11, p < 10(-4)), and 11.2 +/- 3 days in AdSvIL10-infected grafts (n = 11, p < 10(-4)). Histologic scores (blinded) showed significantly (p < 0.005) higher regression coefficients for rejection in controls compared with both cytokine-transduced groups. Perioperative administration of cyclosporine A (INN: ciclosporin) to recipients had no effect on survival of AdCMVTGF-beta-infected grafts but reduced survival of AdSvIL10-infected grafts. CONCLUSIONS: Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts is efficient and effectively prolongs graft survival. Vectors that would induce long-term expression of such genes may make this approach clinically applicable.

Adenoviridae↗
PubMed1997

Controlled periadventitial administration of verapamil inhibits neointimal smooth muscle cell proliferation and ameliorates vasomotor abnormalities in experimental vein bypass grafts.

OBJECTIVE: Inhibition of early myointimal proliferation may improve longterm patency of vein grafts, but the clinical use of many experimental drugs is limited by systemic toxicity. To determine whether this goal can be achieved by low-dose targeted drug administration, we constructed a polymeric system delivering verapamil and evaluated the effects on local and downstream vein graft morphology, neointimal smooth muscle cell proliferation, and vasomotor function. METHODS: Ethylene-vinyl acetate polymeric delivery systems were constructed, containing 2% verapamil by weight. These are flexible, biocompatible, and nonbiodegradable matrices, delivering the drug at a rate of 10 micrograms/day. The autologous external jugular vein was used to create a carotid artery bypass graft in hypercholesterolemic (n = 22) rabbits. Verapamil-containing matrices (n = 12) or plain polymers (control, n = 10) were wrapped around the proximal third of the veins after reperfusion. Graft vasomotor function was evaluated and was also compared with function of an additional group of normocholesterolemic vein grafts (n = 8). RESULTS: Twenty-eight days after grafting, intimal index (intima/media thickness ratio) was 31% lower, neointima/original lumen surface ratio was 26% lower, and residual luminal area was 71% greater (4.00 +/- 1.2 mm2 versus 2.34 +/- 0.9 mm2, all p < 0.01) under verapamil matrices compared with control grafts. Neointimal smooth muscle cell content was reduced from 45.4% to 28.2%, and net neointimal smooth muscle cell thickness was reduced by 47% (30 microns vs 15.8 microns, both p < 0.01). Verapamil-treated segments distal to the matrices also showed significantly lower neointimal smooth muscle cell density and increased lumen size. Sensitivity to serotoin and vasomotor responses to serotonin, norepinephrine, and sodium nitroprusside in distal segments were significantly lower in verapamil-treated grafts than in controls. CONCLUSIONS: Periadventitial controlled administration of verapamil below 1% of the systemic dose effectively inhibits myointimal hyperplasia in vein grafts. Local polymeric drug delivery may be readily applicable to coronary revascularization operations.

Animals↗
PubMed1997

Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts: method and efficacy of adenovirus-mediated transduction.

OBJECTIVE: Allograft-targeted immunosuppressive gene therapy may inhibit recipient immune activation and provide an alternative to systemic immunosuppression. We studied the optimal technique and efficacy of intracoronary gene transfer of viral interleukin-10 and human transforming growth factor-beta 1 in a rabbit model of heterotopic heart transplantation. METHODS: Replication-defective adenoviral vectors were constructed, expressing viral interleukin-10 (AdSvIL10) or transforming growth factor-beta 1 (AdCMVTGF-beta 1). Intracoronary delivery of vectors was accomplished ex vivo by either bolus injection or slow infusion. The allografts were implanted heterotopically in recipient rabbits and collected 4 days after the operation. Vector dose was 4 x 10(9) to 6 x 10(10) pfu/gm of donor heart. Transfer was confirmed by DNA amplification for both genes. Gene product expression in tissue was quantified by immunoassay and visualized by immunohistochemical staining. RESULTS: Allograft viral uptake was only 9.9% +/- 2.4% with bolus injection, but increased to 80.5% +/- 6.8% at 1 ml/min infusion rate (p = 5 x 10(-14)). Uptake ratio was not affected by vector quantity or slower infusion rates. Transforming growth factor-beta 1 was consistently detected in allografts infected with AdCMVTGF-beta 1, but not with control adenovirus or AdSvIL10. Expression was proportional to infused vector quantity and reached 10 ng/gm of allograft at infused 10(10) pfu/gm. Transforming growth factor-beta 1 was also detected in recipient's serum at less than 1 ng/ml. Viral interleukin-10 was detected in minor amounts only (< 1 ng/gm) in allografts infected with AdvIL10 up to 5 x 10(10) pfu/gm. Nevertheless, it was detected in recipient serum at concentrations up to 0.4 ng/ml. CONCLUSIONS: Intracoronary gene transfer of immunosuppressive cytokines to cardiac allografts during cold preservation is feasible. Slow infusion is superior to bolus injection. In vivo effects on allograft rejection remain to be determined.

Adenoviridae↗
PubMed1997

Benefits of early surgical repair in fixed subaortic stenosis.

OBJECTIVES: We sought to determine whether early resection can improve outcome in fixed subaortic stenosis. BACKGROUND: The diagnosis of subaortic stenosis (SAS) is often made before significant gradients occur. Whereas resection is the accepted treatment, it remains uncertain whether surgical intervention at this early stage can reduce the incidence of recurrence or influence the progression of aortic valve damage. METHODS: Follow-up was available for 75 of 83 consecutive patients operated on for fixed SAS; the average duration of follow-up was 6.7 years. The lesion was discrete in 68 patients (91%) and of a tunnel type in 7, with associated ventricular septal defect in 28 (37%). All underwent transaortic resection. RESULTS: There were no deaths. There were 18 recurrences of SAS in 15 patients (20%). Thirteen patients (17%) underwent 17 reoperations for recurrence or aortic valve disease. The cumulative hazard of recurrence was 8.9%, 16.1% and 29.4% +/- 2.3% (mean +/- SEM), and the hazard of events, including recurrence and reoperation, was 9.2%, 18.4% and 35.1% +/- 3.5% at 2, 5 and 10 years, respectively. Residual end-operative left ventricular outflow tract (LVOT) gradients (> 10 mm Hg, n = 8) and tunnel lesions were univariate predictors of recurrence (p = 0.0006 and p = 0.003, respectively). Multivariate predictors included higher preoperative LVOT gradient (p < 10(-4)) and younger patient age (p = 0.002). Only two recurrences (0.87 per 100 patient-years of follow-up) were noted in patients with a preoperative peak LVOT gradient < or = 40 mm Hg (n = 40), whereas higher gradients (n = 35) were associated with a greater than sevenfold recurrence rate (6.45 events per 100 patient-years, p = 0.002). The aortic valve required concomitant repair in 17 cases in the high gradient group (48.6%) but in only 8 in the low gradient group (20%, p = 0.018). Despite relief of the obstruction, progressive aortic regurgitation was noted at follow-up after 14 procedures in the high gradient group (40%) but after only 5 procedures in the low gradient group (12.5%, p = 0.014). CONCLUSIONS: The data suggest that surgical resection of fixed subaortic stenosis before the development of a significant (> 40 mm Hg) outflow tract gradient may prevent recurrence, reoperation and secondary progressive aortic valve disease.

Aortic Stenosis, Subvalvular↗
PubMed1997

Growth after bone marrow transplantation in young children conditioned with chemotherapy alone.

Short stature is a potential side-effect of BMT, brought about by the conditioning protocol and/or the complications of BMT. This study evaluates the effects of conditioning by chemotherapy, and BMT complications on growth. Thirty children conditioned for BMT by chemotherapy alone (cyclophosphamide and busulfan) were classified according to the occurrence of serious or prolonged complications after BMT: group 1 (n = 12) had no complication, while group 2 (n = 18) did. Fifteen of them were severely growth retarded (< or = -2 s.d.) at BMT, because of their initial disease. At the time of BMT, the two groups had similar ages (1.0 +/- 0.2, s.e.m. year, in group 1 and 1.7 +/- 0.5 year in group 2), height (-1.7 +/- 0.5; -1.8 +/- 0.3 s.d.) and plasma insulin-like growth factor I (IGFI) levels (0.3 +/- 0.1 U/ml in both). Group I grew significantly and their plasma IGFI increased but group 2 did not, as assessed 2 years post-BMT. We conclude that conditioning with chemotherapy alone does not prevent the catch-up growth induced by BMT in young children; the lack of catch-up growth is due to complications occurring after BMT, and the change in plasma IGFI suggests that complications of BMT prevent any increase in plasma IGFI, and thereby catch-up growth.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Adult height in 24 patients treated for growth hormone deficiency and early puberty.

This study evaluates the capacity of treatment with the combination of growth hormone (GH) and gonadotropin releasing hormone (GnRH) analog to preserve the height potential of 24 patients (15 girls, 9 boys) with GH deficiency and early puberty (onset at 7.8 +/- 0.5 SE yr in girls and 9.0 +/- 0.7 yr in boys). All but 4 were given cranial irradiation. They (group 1) were compared with 17 patients of normal pubertal age treated with GH for cranial irradiation-induced GH deficiency (group 2) and with 19 girls treated with GnRH analog for idiopathic central precocious puberty (group 3). The adult heights in groups 1, 2 and 3 were -0.5 +/- 0.2, -1.3 +/- 0.2, and -0.2 +/- 0.2 SD, significantly lower (P < 0.01) in group 2. They were lower than the target heights in groups 1 and 2 (P < 0.001), and similar in group 3. They were similar to the predicted heights at the onset of therapy (combined, GH, or GnRH analog therapy), except in group 3 (adult height > predicted height, P < 0.0001) In group 1, as in group 3, the differences between adult and predicted heights (1.1 +/- 1.3 and 6.5 +/- 1.4 cm respectively) correlated positively with the difference between bone and chronological ages (P < 0.05), negatively with the predicted height (P < 0.002), and positively with the difference between the target and predicted heights (P < 0.001) at the onset of therapy. In conclusion, treatment with the combination of GH and GnRH analog in patients with GH deficiency and early puberty leads to a normal adult height. This height is similar to the predicted height at the onset of therapy but lower than the target height.

Adult↗
PubMed1997

Pituitary stalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis.

The detection of pituitary stalk interruption syndrome (PSIS) by magnetic resonance imaging is a diagnostic marker of permanent GH deficiency (GHD), but the pathogenesis of PSIS is unknown. Fifty-one patients (27 males) with GHD and PSIS were classified according to whether the GHD was isolated (group 1, 16 cases) or associated with other anterior pituitary abnormalities (group 2, 35 cases). The 2 groups had similar characteristics (frequencies of perinatal abnormalities, ages at occurrence of first signs and at diagnosis, height, GH peak response to stimuli other than GHRH), but associated malformations were less frequent in group 1 (12%) than in group 2 (54%; P < 0.01), hypoglycemia occurred in 25% of group 1 and 70% of group 2 (P < 0.01), and the GH peak response to GHRH was less than 10 micrograms/L in 0% of group 1 (4 cases evaluated) and 57% of group 2 (21 cases; P < 0.05). Thirty-one cases (61%; 25 from group 2) had features suggesting an antenatal origin: familial form (4 cases), microphallus (10 boys), and/or associated malformations (50%; 21 cases). Twenty-seven cases (53%, 22 from group 2) had features suggesting a hypothalamic origin. The three group 1 patients with a GH peak of 1 microgram/L or less had no large GH-N gene deletion. One familial form had no linkage between the GHD phenotype and abnormal GH-N locus, and the only mutation described to date in the GHRH receptor gene was absent. The two patients with low plasma PRL levels had no Pit-1 gene abnormality. Thus, most of the patients with GHD associated with multiple anterior pituitary abnormalities and PSIS have features suggesting an antenatal origin. The GH-N, GHRH receptor, and Pit-1 genes do not seem to be implicated in PSIS.

Adolescent↗
PubMed1996

Adult height after cranial irradiation with 24 Gy: factors and markers of height loss.

The decrease in adult height of children who have been given cranial irradiation (24 Gy) for acute lymphoblastic leukaemia is attributed to chemotherapy, growth hormone (GH) deficiency and early puberty. This study evaluates the factors involved in the height loss between irradiation and adult height and its markers in 43 patients irradiated at 5.8 +/- 0.4 (SEM) years. The mean height loss was 0.9 +/- 0.2 SD in the children with a normal GH peak (n = 11), 1.7 +/- 0.2 SD in those with a low GH peak and untreated (n = 15) and 0.6 +/- 0.2 SD in those treated with GH (n = 17). The adult height was significantly lower than target height in all three groups. The height loss correlated negatively with the GH peak (p < 0.02) and with the age at onset of puberty (p < 0.05) in the first two groups with spontaneous growth, but not with the chemotherapy regimen or its duration, or the plasma insulin-like growth factor I (IGFI) and its GH-dependent binding protein (BP-3). Early puberty (onset at 8-10 years) occurred in 6 girls from the first two groups. At the first evaluation, 5.6 +/- 0.4 years after irradiation, the GH peak values after arginine-insulin stimulation correlated with the age at irradiation (p < 0.03), taking into account the time since irradiation. The plasma IGFI and BP-3 values were correlated with each other, but not with the GH peak. In conclusion, this study demonstrates the impact of GH deficiency and GH replacement therapy on adult height in children given cranial irradiation for leukaemia. They therefore should be evaluated for their GH secretion 1-2 years after the end of chemotherapy. GH therapy is indicated for those with low GH peak and decreased growth rate or no increase in growth rate despite puberty.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Four families with loss of function mutations of the thyrotropin receptor.

We observed four families with loss of function mutations of the TSH receptor gene. One patient had a homozygous Pro162 Ala substitution. The three other were compound heterozygotes: 1) Gln324-->Stop and Asp410 Asn2), Cys41 Ser and Phe525 Leu, 3) Cys390 Trp and Trp546-->Stop. In all patients, the plasma TSH concentration was increased, whereas T3 and T4 concentrations were normal. The TSH levels were normal in the heterozygous parents. These results confirmed the recessive character of TSH receptor defects. Expression of the various mutated receptors in transfected COS-7 cells demonstrated the impairment of their function. We studied the expression of the receptors on the cell surface by immunofluorescence, their ability to bind hormone, and their capacity to activate adenylate cyclase. Some mutations allowed us to identify sites that are especially important for receptor function. The substitution Cys390 Trp abolished high affinity hormone binding. Receptor mutated at Asp410 Asn bound the hormone normally, but failed to activate adenylate cyclase. This result underscores the role of this acidic extracellular residue, close to the first transmembrane segment, in signal transmission. The Phe525 Leu substitution also markedly impaired adenylate cyclase activation, underlining the importance of the second intracellular loop in receptor signaling.

Adenylyl Cyclases↗
PubMed1995

Surgical management of ventricular septal defect with aortic valve prolapse: clinical considerations and results.

Aortic valve prolapse is found in over 5% of children with ventricular septal defect (VSD). Although this association occurs mostly with doubly committed subarterial VSDs, in this study the predominant type of VSD was perimembranous. In order to determine the need and timing for surgery and whether the anatomical features of septal defect may influence clinical management and outcome in this lesion, we reviewed our experience with 28 consecutive patients, operated on for VSD with prolapsed aortic valve cusp, with or without aortic regurgitation. Twenty-two patients had a perimembranous VSD and six had doubly committed VSD. Aortic regurgitation was trivial or absent in nine patients, mild in ten and moderate to severe in nine. Associated cardiac anomalies were present in 18 patients, all having perimembranous VSD, and included right ventricular outflow tract (RVOT) obstruction (n = 6), discrete subaortic membrane (n = 4) or both (n = 8). None of these patients had more than moderate aortic regurgitation. The patients underwent surgical closure of the septal defect between the ages of 1.5 and 34 years of age (median = 7). Sixteen patients having mild or trivial aortic regurgitation underwent closure of the VSD only, and 12 patients underwent VSD closure with aortic valvuloplasty. Valvuloplasty was required more often in doubly committed VSDs (66%) and in the perimembranous type without associated anomalies (100%), and significantly less often in the presence of RVOT obstruction, subaortic membrane or both (22%). At follow-up (up to 5 years, mean 18 months), the grade of aortic regurgitation was unchanged in 11 and decreased in 5 patients undergoing closure of the VSD only.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

[Hypothalamo-hypophyseal function after treatment of cancers].

Cranial irradiation may result in altered hypothalamo-pituitary function in patients treated for cancer distant from this area. Growth hormone (GH) deficiency is the most frequent complication. The frequency, delay of occurrence and severity of GH deficiency depend on the irradiation dose delivered to this area. The other factors influencing the frequency are the age at irradiation and the fractionation schedule. The frequency of other hypothalamo-pituitary changes is also dose-dependent: thyrotropin and gonadotropin deficiencies occur in 50-60% of cases after 50 Gray, and corticotrophin deficiency in 30%. Low dose cranial irradiation may also induce precocious puberty (onset < 8 yr in girls and < 10 yr in boys). The radiation-induced lesions seem to occur in the hypothalamus rather than in the pituitary. There is generally a good correlation between the GH peak and the growth velocity, but there may be normal growth in spite of GH deficiency after low dose or due to precocious puberty, decreased growth velocity in spite of normal GH peak, due to bone irradiation. Results on final height have been optimized by a better indication of GH therapy and by its association with treatment of precocious puberty.

Child↗
PubMed1994

Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease.

We conducted a prospective, open study of oral itraconazole therapy (5 and then 10 mg/kg per day) to assess tolerance and potential efficacy in preventing fungal infections in patients with chronic granulomatous disease. Thirty-two patients were enrolled in one center between 1985 and 1991. Tolerance was excellent in all cases. Poor compliance was suspected in three cases. Two patients were excluded from efficacy analysis because itraconazole was used as part of therapy for pulmonary aspergillosis. Of 30 patients, 3 developed a fungal (Aspergillus) lung infection, an incidence 3.4/100 patient-years versus 11.5 in a historical control group that did not receive any prophylaxis (p = 0.13) and 9.55 in a historical group of patients who received daily ketoconazole prophylaxis (p = 0.19). The percentage of patients infected with Aspergillus was significantly different: 10% in the itraconazole group versus 34.4% in the untreated group (p = 0.013). These results require further evaluation through a comparative randomized trial to assess the possible benefit of itraconazole prophylaxis in patients with chronic granulomatous disease.

Administration, Oral↗
PubMed1994

True hermaphroditism: genetic variants and clinical management.

The diagnosis and management of 22 patients with true hermaphroditism are described. Sixteen of them were first seen before the age of 4 months. The initial manifestations were ambiguous genitalia in 20 cases (two of them identified prenatally by ultrasound examination), isolated clitoromegaly in one, and penile hypospadias plus unilateral cryptorchidism in one. All patients but one had at least one palpable gonad. Eleven of the twelve patients examined before the age of 6 months had basal plasma testosterone levels > 0.4 ng/ml. In older patients the stimulation test was necessary to demonstrate male testosterone secretion. The most common peripheral karyotype was 46,XX (17 cases); the other karyotypes were 47,XXY (1 case) and mosaicism 46,XX/46,XY (2 cases) or 46,XX/47,XXY (2 cases). One of the patients with the 46,XX karyotype had 46,XX/46,XY on fibroblast culture; four had the SRY gene in their leukocytes and one in the tissue taken at gonadal biopsy. A vagina was found in all patients at laparotomy, and a uterus was found in 17 cases (as a hemiuterus in 9). Genitography failed to demonstrate a uterus in only one case. The testicular tissue was dysgenetic but the ovarian tissue was normal. Sex assignment was male in 8 patients (reoriented by us in 2) and female in 14 patients (reoriented by us in 3). Spontaneous pubertal development occurred in the 4 patients (2 boys, 2 girls) with gonadal tissue who reached pubertal age. We conclude that true hermaphroditism is a heterogeneous condition in terms of its genetic background, with a prevalence of the 46,XX karyotype. There may be mosaicism with a Y-bearing cell line limited to the gonad (its frequency is probably underestimated), a paternal meiotic exchange between X and Y occurring in 46,XX cases with SRY, or a lack of the SRY gene, suggesting that other genes working independently of SRY may also determine testicular differentiation.

Child↗
PubMed1994

Diagnostic markers of permanent idiopathic growth hormone deficiency.

Idiopathic GH deficiency is a clinically and biologically heterogeneous condition. We have attempted to improve its diagnosis by analysing the status of 52 patients, aged 0.1 to 17.5 yr, with GH peak responses after 2 pharmacological stimulation tests of less than 10 micrograms/L. Group 1 (n = 24) had certain GH deficiency because of pituitary stalk interruption syndrome, familial form, and/or microphallus and hypoglycemia. Group 2 (n = 13) had transient GH deficiency. The diagnosis remained uncertain in group 3 (n = 15). The control group (n = 77) had prepubertal idiopathic short stature. Growth failure began before 5 yr of age in 88% of group 1, 18% of group 2, and 33% of group 3 patients. The mean GH peaks and the numbers of patients with GH peaks below 7 or 7-10 micrograms/L were similar in the three groups. Levels of plasma insulin-like growth factor-I (IGF-I) and its binding protein-3 (BP-3) were significantly lower in group 1 than in groups 2 and 3 (P < 0.001) or in children with idiopathic short stature (P < 0.01). When the results of these two parameters were combined, only one patient with certain GH deficiency had normal values, but only one severely undernourished young child with transient GH deficiency had values below the lower limit for children with idiopathic short stature. The diagnosis for group 3 remained uncertain, even after spontaneous pubertal development (n = 4), as the GH peak was 4.5-10.7 micrograms/L and plasma IGF-I was normal in three cases, and BP-3 was normal in four cases. We conclude that certain GH deficiency is distinguished from transient GH deficiency by age at onset and plasma IGF-I and BP-3 levels. Many patients diagnosed as GH deficient had normal for age plasma IGF-I and BP-3 levels, indicating transient GH deficiency in many of them.

Aging↗
PubMed1994

Management of the short stature due to pubertal delay in boys.

Boys with constitutional pubertal delay who present with decreased growth rate pose diagnostic and therapeutic problems. Ninety-one boys seen after the age of 14 yr for height for age less than -2 SD, growth rate less than 5 cm/yr, and pubertal delay were evaluated. The GH peak after the arginine-insulin stimulation test was less than 10 micrograms/L in 35 of the subjects; these boys differed from the 56 others in having a GH peak of 10 micrograms/L or more, their higher body mass index (-0.27 +/- 0.2 vs. -0.85 +/- 0.1 score; P < 0.05), and lower plasma insulin-like growth factor-I (IGF-I; 1.2 +/- 0.2 vs. 1.8 +/- 0.2 U/mL; P < 0.05). The GH peak correlated negatively with the body mass index (P < 0.01), but not with plasma levels of testosterone and IGF-I or its GH-dependent binding protein (BP-3). At a second GH evaluation, performed with testosterone priming (21 boys; 100 mg testosterone heptylate/15 days, im; four doses) or without (6 boys), 23 patients had increased their GH peak to above 10 micrograms/L, and 4 had not. Three of these were treated with human (h) GH, and a third GH evaluation, performed after full pubertal development, showed a normal GH peak. The growth rate during the year preceding the GH evaluation was 3.8 +/- 0.1 cm (1-7 cm). During the year after the GH evaluation, it was 6.8 +/- 0.3 cm in the 32 patients followed without therapy, 7.3 +/- 0.3 cm in the 25 patients given testosterone (25 mg testosterone heptylate/15 days, im), and 7.3 +/- 1.4 cm in the 3 treated with hGH. Spontaneous growth during the 2 periods was correlated with testicular volume (P < 0.01) and the plasma testosterone level (P < 0.05), but not with the GH peak, plasma IGF-I, or BP-3. The final height (n = 49) was -1.0 +/- 0.1 SD, below target height (-0.4 +/- 0.1 SD; P < 0.0001). It was similar in patients with a GH peak below or equal to or above 10 micrograms/L and in those given or not given testosterone therapy. We conclude that the growth rate of boys with constitutional pubertal delay depends on the testicular volume and plasma testosterone level, but not on the GH peak, plasma IGF-I, or BP-3 levels. Final height is not altered by a transient drop in GH or by low dose testosterone therapy.

Adolescent↗
PubMed1994

Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy.

We studied the GH-insulin-like growth factor-I (IGF-I) axis serially over 24-36 months in six patients with medulloblastoma who underwent surgical removal of the tumor followed by craniospinal irradiation therapy for 6 weeks and then chemotherapy for 42 weeks. Eighteen and 24 months after beginning irradiation there was a decline in the peak GH secretory response to acute stimulation with arginine/insulin hypoglycemia. Six months after irradiation and during chemotherapy there was a transient decline in IGF-I, IGF binding protein-3 (IGFBP-3), and GH-BP values (respective mean values of 56.1 +/- 9.0 ng/mL, 1.1 +/- 0.2 microgram/mL, and 7.6 +/- 3.3% of radioactivity as compared to time 0 values: 13%%o/- 15 ng/mL, 2.2 +/- 0.2 micrograms/mL, and 20.0 +/- 4.0%, P < 0.001), although provoked GH secretion was normal at this time. The IGF-I, IGFBP-3, and GH-BP returned to pretreatment ranges by 12-36 months after initiation of the study. There was also a decline in body mass index and serum protein values at 6 months, suggesting suboptimal nutrition during this period. Six months after irradiation in ligand and immunoblot analysis there was a decline in IGFBP-3 and an abnormal electrophoretic mobility of IGFBP-2 that were both normalized at 36 months. In one patient we observed a high level of IGFBP-3 proteolysis at this time. This study demonstrates that before the decrease of GH secretion in patients receiving cranial irradiation there is a transient phase of GH insensitivity that may be characteristic of the acute therapeutic phase including the chemotherapy. This partial insensitivity may explain the early growth retardation observed in these patients.

Adolescent↗