Untreated Boys Research Articles

Long-term Results of Treatment With Low-Dose Fluoxymesterone in Constitutional Delay of Growth and Puberty and in Genetic Short Stature

This prospective study was designed to assess growth response, side effects, other possible long-term effects, and final adult height in boys treated with the oral androgen, fluoxymesterone. From 1973 to 1984, eighty-two short boys (71 with constitutional delay of growth and puberty [CDGP] and 11 with genetic short stature [GSS]) were treated with daily oral doses of 2.5 mg of fluoxymesterone from 6 to 60 months. Final height assessment was made from 1989 to 1991. A group of 34 untreated boys (26 with CDGP and 8 with GSS) were also followed to assess the accuracy of the Greulich-Pyle and Bayley-Pinneau (GP-BP) and sexual maturity index height prediction methods. During treatment, each patient had a 1.7- to 2.5-fold increase in linear growth velocity. Accelerated velocity (over baseline) continued as long as the bone age was less than 14 years. No adverse androgenic effects (or undue acceleration of puberty) were observed. Final height exceeded pretreatment predictions for CDGP + GSS by 6.1 +/- 3.5 (SD) cm (GP-BP) and 5.4 +/- 3.2 cm (sexual maturity index). It is concluded that a daily oral dose of 2.5 mg of fluoxymesterone can be used to accelerate linear growth in boys with CDGP and GSS when needed to alleviate emotional problems secondary to slow growth and short stature without fear of compromising final adult height.

Cognitive)ehavioral intervention with aggressive boys: Three-year follow-up and preventive effects.

This study examined the longer term preventive effects of a school-based intervention with boys referred by classroom teachers as highly aggressive and disruptive. Three years after intervention, boys who had received an anger coping (AC) program were compared with a group of untreated boys. The AC boys had lower rates of drug and alcohol involvement and had higher levels of self-esteem and social problem-solving skills. The AC boys were not significantly different from previously nonaggressive boys on these variables at follow-up. Although the overall intervention did not have longer term effects on delinquency rates or classroom behavior, a subset of boys who also received booster sessions did display maintenance of certain classroom behavior improvement. Implications for intensification of cognitive-behavioral interventions are discussed.

Consistently normal CD4+, CD8+ levels in haemophilic boys only treated with a virally safe factor VIII concentrate (BPL 8Y)

Prospective biochemical, virological and selected immunological follow up has been done for up to 32 months on 15 previously untreated haemophilic boys following treatment with an intermediate purity dry heated factor VIII concentrate (BPL 8Y). Tests for liver function and antibodies to blood-borne viruses have been assessed monthly for the first year after starting treatment and thereafter every 2 months. All patients were immunized against hepatitis B and have not developed hepatitis B core antibodies and no boy has shown any rise in alanine transaminase level nor has anyone developed antibodies to hepatitis C (HCV). All patients have remained anti-HIV seronegative. T lymphocyte subsets have been measured approximately every 4 months and in no patient has there been a significant rise in CD8+ cells; one patient showed a significant decrease in CD4+ cells but these and all CD4+ values for the other boys remained within normal age related limits. Changes in CD4+ levels in this one boy were not related to the total amount of treatment received. This group of patients who appear not to have contracted HIV, hepatitis B or non A non B hepatitis following treatment with this intermediate purity factor VIII concentrate have also not shown any consistent changes in CD4+ or CD8+ cells, which have been recorded previously in frequently treated haemophiliacs.

Vitamin D metabolism in chronic childhood hypoparathyroidism: Evidence for a direct regulatory effect of calcium

We noted the presence of elevated levels of circulating 1,25-dihydroxyvitamin D (83 pg/ml (200 pmol/L), with low total serum calcium concentration (6.5 mg/dl (1.88 mmol/L), in an untreated adolescent boy with hypoparathyroidism. Furthermore, an inverse relationship between total serum calcium and circulating 1,25-dihydroxyvitamin D levels was evident during treatment with 1,25-dihydroxyvitamin D3. We examined this relationship with a 33-hour intravenous infusion of calcium gluconate in the absence of exogenous 1,25-dihydroxyvitamin D3 therapy. The infusion was accompanied by a gradual increase of both total serum calcium and blood ionized calcium concentrations from hypocalcemic to normocalcemic ranges, and produced a 50% reduction in circulating 1,25-dihydroxyvitamin D values, with minimal changes in circulating phosphorus, magnesium, and 25-hydroxyvitamin D values. These results suggest that calcium-dependent, parathyroid hormone-independent regulation of 1,25-dihydroxyvitamin D production may exist in human beings.

Safety trial of heated factor VIII concentrate (8Y).

Seventeen previously untreated boys with haemophilia A were treated with high purity heat treated factor VIII concentrate (8Y) for up to 36 months. Liver function tests were assessed monthly. No boy's serum has been shown to contain HIV antibodies and no increases in alanine transaminase activity have been detected. In only one patient was a single rise in aspartate transaminase activity noted, and this was without a corresponding rise in alanine transaminase. A second patient's serum contained hepatitis B core antibody transiently. It was thought likely in both cases that the abnormalities reflected intercurrent infections rather than disease associated with transfusion. The physical treatments used in the production of 8Y seem to inactivate the agent(s) responsible for non-A, non-B hepatitis and HIV transmission by transfusion of factor VIII has been abolished. There are, however, problems associated with conducting safety trials in young haemophiliac patients.

Influence of hCG treatment on the metabolism of progesterone and pregnenolone in vitro by the human undescended prepubertal testis.

Testicular biopsies were taken from 56 prepubertal and pubertal boys, aged 3-17 years, with undescended testes. The biopsies were incubated in vitro with 3H-progesterone or 3H-pregnenolone. Fifteen of the boys had been treated with human chorionic gonadotrophin (hCG) prior to operation. Nine boys were operated on within 1 week of the last injection of hCG while the others were operated on between 12 days and 2 years after hCG treatment. In non-treated prepubertal boys very small amounts of substrate were converted by means of the enzymes 3 beta-hydroxysteroid-dehydrogenase and 17 alpha-hydroxylase and virtually no testosterone was produced. Immediately after treatment with hCG there was a large increase in the conversion of substrate by 17 alpha-hydroxylase and 3 beta-hydroxysteroid-dehydrogenase. Considerable amounts of testosterone were formed, especially from pregnenolone, while smaller amounts were formed from progesterone. This suggests that testosterone production occurred primarily via the delta 5 pathway, at least beyond the 17 alpha-hydroxylase-step. Within 2 weeks of the last hCG injection, steroidogenic activity had decreased towards levels similar to those found in prepubertal testis from untreated boys. These observations indicate that hCG treatment of boys with undescended testes does not result in irreversible or even long-lasting stimulation of their steroidogenic function.

Bromocriptine treatment in adolescent boys with familial tall stature: a pair-matched controlled study.

Recently, bromocriptine has been proposed as a novel agent for the treatment of excessively tall stature in adolescents. To further test its value, we treated nine boys, aged 10.0-15.4 yr, for 1 yr with bromocriptine (7.5 mg/day). A paradoxical plasma GH response to TRH was demonstrated in four of eight boys before and in five boys after 6 months of bromocriptine treatment. At the onset of therapy, the mean adult height prediction was 202.2 +/- 4.3 (+/- SD) cm (Bayley-Pinneau), 202.1 +/- 4.7 cm (TW Mark II), and 198.6 +/- 5.3 cm (Roche-Wainer-Thissen). After 1 yr of therapy, the mean adult height prediction had changed by -4.5 +/- 2.6 cm (Bayley-Pinneau), -3.4 +/- 2.2 cm (TW Mark II), and -2.6 +/- 1.2 cm (Roche-Wainer-Thissen). These reductions were solely due to a decrease in growth velocity and not to an increased skeletal maturation rate. To substantiate these findings, each treated boy was pair-matched with an untreated tall boy so that their chronological and skeletal ages differed by less than 1 yr. After 1 yr of follow-up, height predictions in the treated boys compared with those in the matched control boys gave significantly reduced results with the Bayley-Pinneau and the Roche-Wainer-Thissen, but not with the TW Mark II, method. Because of this discrepancy it is uncertain whether final height in tall boys will really be reduced by treatment with bromocriptine.

BROMOCRIPTINE (BRC) TREATMENT IN EXCESSIVELY TALL BOYS. A PAIR-MATCHED CONTROLLED STUDY

Recently, BRC has been proposed as a novel agent for the treatment of tall stature in adolescents based on its ability to reduce adult height prediction (HP). Eight boys with a chronological age of 10.3-15.4 yrs (mean 13.3 yrs) were treated for 1 yr with BRC 7.5 mg daily. At the onset of therapy, adult height prediction according to Bayley-Pinneau (HP-BP) was 200.7 to 209.7 cm and according to Tanner Mark II (HP-TWII) 199.0-211.5 cm. After 1 yr of therapy, HP with both methods had decreased in every boy, changing by -4.13±1.86(SD) cm (HP-BP) or -3.35±2.39(SD) cm (HP-TWII), respectively. To substantiate these findings, each patient was pair-matched with a control, an untreated boy with a height above +2SDS and a bone age differing less than 0.5 yr. HP-BP was significantly reduced in patients after 1 yr of BRC compared with their matched controls after 1 yr of follow-up (p less than 0.02). By contrast, differences in HP-TWII were not significant. Because of this discrepancy it is uncertain whether final height in tall boys will really be reduced by treatment with BRC. BRC was kindly provided by Dr. R. Schmidt, Sandoz Ltd.

Client characteristics associated with behavior change for treated and untreated aggressive boys.

This study examined the relationship between subject characteristics of aggressive boys and their behavioral changes during a school year. Seventy-six boys in the fourth, fifth, and sixth grades were identified by their teachers as the most disruptive and aggressive in their classes. These boys were assigned to untreated control, anger-coping, anger-coping plus goal-setting treatment, and minimal treatment goal-setting cells. The anger-coping treatment was based on cognitive behavioral procedures. In both anger-coping cells, greater reductions in rates of disruptive/aggressive off-task classroom behavior was predicted by having higher rates of these behaviors initially, and greater reductions in parents' ratings of aggression was predicted by having poor social problem-solving skills initially. Additional predictors of reductions in parents' ratings of aggression in one, but not both, anger-coping cells included having higher rates of somatic symptoms and poorer social acceptance by peers. In contrast to the other cells, those boys in the no-treatment group who demonstrated the greatest spontaneous improvement on these change measures were the ones who initially were the best problem-solvers and who had higher levels of self-esteem. This cognitive-behavioral treatment appeared to have most impact with those boys who were the most in need of intervention.

IMMUNOREGULATION IN AN ISOLATED 12-YEAR-OLD BOY WITH CONGENITAL SEVERE COMBINED IMMUNODEFICIENCY

We report the evaluation of in vitro immunoregulation in a 12-year-old untreated boy with severe combined immunodeficiency (SCID). Severely hypogammaglobulinemic, the patient was incapable of a specific antibody response to either natural substances or administered antigens. Ficoll-Hypaque-isolated peripheral blood mononuclear cells (MNL) from the patient failed to respond to pokeweed mitogen (PWM) with the normal increment in immunoglobulin-secreting cells (Ig-SC), as measured by a reverse hemolytic plaque assay. Since the patient was lymphopenic, his MNL were relatively enriched for monocytes (range = 51-81%). Removal of phagocytic cells or the addition of unrelated irradiated helper T lymphocytes resulted in enhanced, but still suboptimal response to PWM, suggesting some intrinsic defect in B lymphocyte function. Co-culture of patient MNL with normal MNL resulted in marked suppression (12% of predicted) of PWM-induced Ig-SC. Suppressor activity was unaffected by prior irradiation of patient MNL, but was substantially reversed (99% of predicted) by removal of his phagocytic cells; whereas the combination of the two procedures further reversed suppression (184% of predicted). The patient's MNL consistently demonstrated subnormal percentages of T3+ and T4+ cells and subnormal to low normal percentages of T8+ cells. These data suggest both an intrinsic defect in B lymphocyte function, and a relative excess of monocytes which could further inhibit Ig secretion by B lymphocytes. Natural killer cell function was severely depressed.

Acceleration of delayed growth with fluoxymesterone.

61 boys with constitutional delay of growth and maturation, aged 9-19 years and with a bone age (BA) lag of 1.3-5.5 years, were administered fluoxymesterone (0.05-0.24 mg/kg daily orally, relative dose increasing with age) to accelerate growth. The therapy was continuous and lasted 0.4-3.6 years. The findings are compared with 37 observation periods in a similar group of untreated boys. Growth velocity increased in every treated boy during the therapy, the mean first-year increment being 4.3 +/- 1.6 cm/year. For most boys this brought about a decrease in the height difference from peers, and so afforded the psychosocial relief that was the objective of the therapy. After therapy the velocity decreased slightly in most boys, from a mean of 9.1 +/- 1.4 to 7.1 +/- 3.3 cm/year. The effect of the intervention on final height was assessed by three relatively independent methods of prediction. These were found to be equally valid in the 15 control boys for whom final heights are known. The effect appeared to vary individually, but on the average there appeared to be no loss of height potential. No individual boy with initial BA greater than 10.5 years showed a substantial reduction in predicted final height.

Gender stereotypy in gender-dysphoric young boys.

This study examined the effects of behavioral treatment of 22 gender-dysphoric boys on measures of male- and female-role stereotyped behavior. The sample included 10 treated and 4 untreated gender-dysphoric boys and 8 normal boys. The findings show no such effect and no evidence of a masculinizing enhancement or a feminizing extinction of behaviors following behavioral treatment of gender-disturbed boys (contrary to statements by critics of the process).

902 MONOCYTE SUPPRESSION OF IMMUNOGLOBULIN SECRETION IN A 9-YEAR-OLD BOY WITH SCID

We report the evaluation of in vitro immunoregulation in a 9-year-old untreated boy with SCID. Ficoll-Hypaque-isolated peripheral blood mononuclear cells (MNL) from the patient failed to respond to pokeweed mitogen (PWM) with the normal increment in immunoglobulin-secreting cells (Ig-SC), as measured by a reverse hemolytic plaque assay. Removal of phagocytic cells or the addition of unrelated irradiated helper cells resulted in enhanced, but still suboptimal response to PWM, suggesting some intrinsic defect in B-cell function. Co-culture of patient with normal MNL resulted in marked (88%) suppression of PWM-induced Ig-SC. Suppressor activity was unaffected by prior irradiation of patient MNL, but was substantially reversed (32% net enhancement) by removal of his phagocytic cells; whereas the combination of the two procedures further reversed suppression (52% net enhancement). Because the patient was lymphopenic, his MNL were relatively enriched for monocytes (range=40-80%). To determine whether the suppressor cell activity was due to functional or numerical excess of patient monocytes, co-cultures were performed using varying ratios of patient to normal MNL. Suppression was most marked in cultures containing >40% monocytes, suggesting that a numerical excess of patient monocytes could account for the observed suppression. These data suggest both an intrinsic defect in B-cell function, and a relative numerical excess of monocytes which could further inhibit Ig-secretion by B-cells.

Statural growth and serum-P in hypophosphataemic rickets: 41

Top of pageAbstract In cross-sectional studies the average height of 37 untreated boys and girls with X-linked hypophosphataemic rickets (X-LH) between 1 and 13 years of age was 2 standard deviations below the normal mean, but there was no relation between height and serum-P in single determinations (Steendijk and Latham, Helv Paed Acta 26: 179, 1971). Sustained increased growth rates have only rarely been observed during therapy with high doses of vitamin D or dihydrotachysterol, and it is not known whether those occurred following a sustained rise in serum-P. Catch-up growth during treatment with oral phosphate supplements, causing a rise in serum-P, has more often been seen, but only in short-term studies. To establish a relation between the level of serum-P during childhood and adolescence, and adult height in a long-term longitudinal study 8 patients with X-LH were followed for periods of 12 to 17 years until adult height had been reached. The patients were treated with dihydrotachysterol in high doses but did not receive phosphate supplements. Since serum-P was not constant during the years of treatment it was necessary in every patient to derive an average value from the serum-P determinations. This was done in the following manner: serum-P was determined at least 4 times per year in each patient, and the average serum-P value per year of age was calculated. From these mean values, the average serum-P (av. serum-P) for the whole period of observation was determined. This final value was correlated with adult height, expressed as standard deviation score (SDS). The coefficient of correlation (r) was 0.789 (p < 0.05) and the regression equation was: Height (SDS) = 7.64 × av.serum-P - 24.51 Av. serum-P ranged from 2.77 to 3.17 mg/100ml and adult height ranged from 0.04 to -3.34 SDS. Within this range of values a reduction of av.serum-P by as little as 0.1 mg/100ml would entail a reduction of adult height by 0.77 SDS (1 SDS equals 6.8 cm in men and 6.2 cm in women). This relatively large effect of a small change in serum-P may help to explain why a relation between serum-P and height has not been found before.

Interrelation of the therapeutic effects of growth hormone and testosterone on growth in hypopituitarism

The present study evaluates the modifying effect of growth hormone on the growth-promoting action of testosterone in boys at pubertal bone age. Growth and bone maturation were analyzed in 42 boys with primary or secondary Leydig cell insufficiency who had been treated with testosterone in an attempt to induce puberty and the accompanying growth spurt. The dosage given was considered normal or high for physiologic replacement therapy at puberty. Sixteen boys had normal GH secretion (seven had isolated gonadotropin deficiency, nine had congenital anorchia); 26 were GH and Gn deficient (20 idiopathic, six craniopharyngiomas). Of the GH-deficient patients, 12 received hGH simultaneously, while 14 received only testosterone. Results from each group were compared with the normal pubertal growth spurt in 15 untreated healthy boys. In isolated Gn deficiency and in congenital anorchia, the growth rates increased to above normal during the first six months of treatment, indicating that the testosterone dosage was probably too high for the beginning of puberty. During two subsequent six-month treatment periods, the rates leveled off close to normal. The same was true in the GH- and Gn-deficient patients on adequate hGH replacement. For contrast, there was minimal or no stimulation of growth when an even higher testosterone dose was given to GH- and Gn-deficient boys without hGH therapy. Bone maturation was normal in the boys with normal GH secretion or with hGH replacement, but was subnormal in the GH-deficient boys not treated with hGH. We conclude that testosterone exerts its full growth-promoting action only in the presence of normal endogenous GH secretion or with sufficient hGH replacement and that both hormones should be continued simultaneously until final adult height is achieved.

98: Voice frequency during normal and retarded growth, and during androgen treatment

We have measured basal, lowest and highest voice frequency (BF, LF, HF), using a simple method, in (1) 372 normal subjects: children and adolescents at ages 6, 8 and 10 years and at the different pubic hair stages (PH), and adults; (2) 71 children with different types of growth failure, and (3) 48 boys with delayed growth and maturation and 31 girls with Turner's syndrome, during fluoxymesterone treatment. BF fell in boys between ages 8 and 10 years (from 259 to 247Hz), but not in girls (253Hz). LF fell between ages 6 and 10 years in boys (from 234 to 203Hz) and girls (from 230 to 218 Hz), and a sex difference appeared. In puberty, a gradual fall of BF and LF occurred parallel to PH development, both in boys (to 100, 90Hz) and girls (to 213, 180Hz). An abnormally high BF was observed in 3 of 12 hyposomatotropic children, 4 of 7 children with Mulibrey nanism, and 2 of 9 children with other prenatal growth failure. Boys with delayed maturation had subnormal BF at PH 1 prior to treatment. At PH 2, fluoxymesterone (0.135mg/kg/day) treated boys had lower BF than untreated boys. Girls with Turner's syndrome also had slightly subnormal BF for PH after fluoxymesterone (0.10mg/kg/day). The voice effect was individually variable. In some cases androgen was discontinued because of voice change and a recovery was observed. The method is useful in the clinical characterization of growth failure and stage of puberty. It is particularly recommended for voice monitoring during androgen treatment when a change is undesirable.