Intradermal transgenic expression of granulocyte-macrophage colony-stimulating factor induces neutrophilia, epidermal hyperplasia, Langerhans'' cell/macrophage accumulation, and dermal fibrosis

Bone age maturation and growth velocity were analyzed longitudinally by the TW2 RUS method standardized for Japanese children in 45 GH-treated boys with idiopathic GH deficiency (GHD). The patients were divided into three groups: Group I consisted of four isolated GHD patients who underwent spontaneous puberty without gonadotropin suppression treatment (GST) and had a mean final height of 151.9 cm; Group II consisted of 24 GHD patients with associated gonadotropin deficiency who received sex hormone replacement treatment (GRT) and had a mean final height of 165.3 cm; Group III consisted of 17 isolated GHD patients who underwent spontaneous puberty and had a mean final height of 158.3 cm after being treated with combined GH and GST. Bone age matured along with chronological age in Group I, whereas bone age in Group II decelerated significantly after a bone age of 12 years and did not reach a bone age of 14 years. Bone age maturation in Group III showed an intermediate pattern between Groups I and II; bone age decelerated significantly after a bone age of 12 years but mean bone age advanced beyond a bone age of 14 years. Height velocity in Group I during GH treatment decelerated rapidly after the pubertal growth spurt, as usually seen in normal puberty. A definite pubertal growth spurt was not observed in the height velocity of Group II during GH treatment before receiving GRT; the mean height velocity gradually declined, remaining at 3.5-4.5 cm/year even after 18 years. Mean height velocity in Group III during GH treatment and GST showed a similar tendency as Group II, but it declined more rapidly. Since a growth velocity of around 3 cm/year was preserved with GH treatment despite the decline in growth velocity, the slower the advance of bone age, the longer the treatment period and, therefore, the taller the final height achieved by GST compared to Group I. It is recommended to start GST at a bone age between 11.5 years and 13 years. The timing, namely when to start GRT in GHD with gonadotropin deficiency or when to stop GST in isolated GHD, can be estimated according to the patient's desired final height and bone age-growth potential.     

Adult height in girls with idiopathic true precocious puberty

GnRH analogs are used to suppress pituitary-gonadal activity in children with true precocious puberty. The indications for therapy in this situation are not established, as some girls have a slow evolutive form, and the capacity of GnRH analogs to preserve the adult height has not been evaluated. This study analyzes the growth and adult heights of 2 groups of girls with idiopathic true precocious puberty, 1 with a predicted height of 155 cm or less (group 1, 19 cases) and the other with a predicted height of more than 155 cm (group 2, 15 cases). Group 1 patients were treated with a long-acting GnRH analog (D-Trp6-GnRH), and group 2 patients were followed without therapy. Group 1 showed greater clinical signs of estrogenization, vaginal maturation index (P < 0.03), plasma estradiol (P < 0.0004), and ratio of LH/FSH peaks (P < 0.01) at the initial evaluation than did group 2. The mean target heights were similar (difference, 0.9 cm). In group 1, the adult height (159 +/- 1.1 cm) was greater than the predicted height before therapy (152 +/- 1.4 cm; P < 0.0001). The difference between the adult height and the predicted height before therapy (mean, 6.5 cm) correlated positively with the bone age advance (P < 0.01), negatively with the predicted height (P < 0.05), and positively with the difference between the target and predicted heights (P < 0.001) before therapy. In group 2, the adult height (162 +/- 1.4 cm) was similar to the predicted height at the initial evaluation (162.5 +/- 1.4 cm). Adult heights correlated with target height in group 1 and with predicted height at the initial evaluation in group 2. In conclusion, some girls with true precocious puberty and poor adult height prediction who are treated with GnRH analog achieve an adult height more comparable to their target height. However, the lack of effect on height in girls with predicted height at the onset of therapy similar to their target height and preservation of the growth potential in the slow evolutive forms suggest that these forms might not require immediate therapy. Careful follow-up before therapy may be a better way of evaluating their natural course.     

Accuracy of final height prediction and effect of growth-reductive therapy in 362 constitutionally tall children

Height reduction by means of treatment with high doses of sex steroids in constitutionally tall stature (CTS) is a well known, though still controversial, therapy. The establishment of the effect of such therapy is dependent on the height prediction method applied. We evaluated the reliability of various prediction methods together with the subjective clinician's judgment in 143 untreated children (55 boys and 88 girls) with CTS and the effect of height-reductive therapy in 249 tall children (60 boys and 159 girls) treated with high doses of sex hormones (cases). For this purpose, we compared the predicted adult height with the attained height at a mean adult age of 25 yr and adjusted the therapeutic effect for differences in bone age (BA), chronological age (CA), and height prediction between untreated and treated children. At the time of the height prediction, controls were significantly shorter, had more advanced estimated BAs (except for the BA according to Greulich and Pyle in boys), had lower target heights, and had smaller adult height predictions compared with the CTS patients (P < 0.05). At the time of the follow-up, CTS patients were significantly taller than controls for both boys and girls (P < 0.02). In controls, a large variability was found for the errors of prediction of the various prediction methods and in relation to CA. The prediction according to Bailey and Pinneau systematically overestimated adult height in CTS children, whereas the other prediction methods (Tanner-Whitehouse prediction and index of potential height) systematically underestimated final height. The mean (SD) absolute errors of the prediction methods varied from 2.3 (1.8) to 5.3 (4.3) cm in boys and from 2.0 (1.9) to 3.7 (3.5) cm in girls. They were significantly negatively correlated with CA (r = [minus 0.27 to -0.65; P < 0.05), except for the Tanner-Whitehouse prediction in boys, indicating that height prognosis is more reliable with increasing CA. In addition, experienced clinicians gave accurate height predictions by evaluating the growth chart of the child while taking into account various clinical parameters, such as CA, BA, and pubertal stage. The effect of sex hormone therapy was assessed by means of multiple regression analysis while adjusting for differences in height prediction, CA, and BA at the start of therapy between treated and untreated children. The mean (SD) adjusted effect varied from -0.5 (2.4) to 0.3 (1.4) cm in boys and from -0.6 (2.1) to 2.4 (1.4) cm in girls. The adjusted height reduction was dependent on the BA at the time of start of sex hormone therapy and was more pronounced when treatment was started at a younger BA. In boys, the treatment effect was significantly negative at BAs exceeding 14-15 yr. After cessation of therapy, additional mean (SD) growth of 2.4 (1.2) and 2.7 (1.1) cm was observed for boys and girls, respectively. The mean (SD) BA according to Greulich and Pyle at that time was 17.1 (0.7) yr for boys and 15.2 (0.6) yr for girls. These data demonstrate that height prediction in children with CTS is inaccurate in boys, but clinically acceptable in girls. With increasing age, height prognosis became more accurate. Overall, the height-reducing effect of high doses of sex hormones in children with CTS was limited, especially in boys. However, a significant effect of treatment was observed when treatment was started at BAs less than 14-15 yr, depending on the method of BA assessment. In boys, treatment appeared to be contraindicated at BAs older than 14-15 yr, because androgen administration caused extra growth instead of growth inhibition. It is recommended that referral should take place early, preferably before puberty, for careful monitoring of growth and height prediction. Moreover, it is recommended not to discontinue therapy before complete closure of the epiphyses of the hand has occurred to avoid considerable posttreatment growth.     

Height, weight and menarche in Swedish urban school children in relation to socio-economic and regional factors

During the period 1964-1973, a defined sample of 740 Swedish urban school children (360 girls and 380 boys) from 40 different urban areas all over the country were followed longitudinally. Height and weight were measured twice a year and age at menarche was recorded. Mean ages at peak height velocity (PHV) and peak weight velocity (PWV) were 11-91 years (SD 0-95) and 12-50 years (SD 1-08) for girls with average values of 8-30 cm/year (SD 1-32) and 7-37 kg/year (SD 1-94). Mean age at menarche was 13-05 years (SD 1-03). PHV and PWV in boys occurred on average at 14-09 years (SD 1-11) and 14-30 years (SD 1-11) with magnitudes of 9-84 cm/year (SD 1-40) and 9-07 kg/year (SD 2-04). No significant differences between socio-economic strata defined by father's occupation and family income were found either for height and weight or for ages at PHV, PWV and menarche. Girls but not boys in the lowest social group (III) had more weight for height during puberty than had girls in social groups I and II. Between the three main geographical regions of Sweden some differences were found. Boys in the South were at the ages of 17 and 18 on average heavier than boys from the rest of the country. Boys and girls in the South had PHV, PWV and menarche half a year later than children in Middle Sweden. In analysis of variance for age at PHV significant interaction terms were found for regions times urbanization. In the South and North age at PHV was earlier the higher the urbanization level, but in Middle Sweden the reverse occurred.     

Emotional status does not alter exercise tolerance in patients with chronic obstructive pulmonary disease

Major changes in bone mineral density (BMD) and body composition occur during puberty. In the present longitudinal study, we evaluated BMD and calculated volumetric BMD [bone mineral apparent density (BMAD)], bone metabolism, and body composition of children (32 girls and 2 boys) with central precocious and early puberty before and during treatment with GnRH agonist (GnRH). Patients were studied at baseline and during treatment for 6 months (n = 34), 1 yr (n = 33), and 2 yr (n = 16). Lumbar spine and total body BMD and body composition were measured with dual-energy x-ray absorptiometry. The variables were compared with age- and sex-matched reference values of the same population and expressed as SD score (SDS). Bone age was assessed. Serum calcium, phosphate, alkaline phosphatase, osteocalcin, the carboxyterminal propeptide of type I collagen (PICP), cross-linked telopeptide of collagen I (ICTP), 1,25 dihydroxyvitamin D and urinary hydroxyproline/creatinine, and calcium/ creatinine ratios were measured. Mean lumbar spine BMD SDS was significantly higher than zero at baseline (P < 0.02) and did not differ from normal, after 2 yr of treatment. Mean spinal BMAD SDS and total body BMD SDS were not significantly different from zero at baseline and had not changed significantly after 2 yr of treatment. During therapy, fat mass and percentage body fat SDS increased, whereas lean tissue mass SDS decreased. Mean lumbar spine BMD and BMAD and total body BMD SDS, calculated for bone age, were all lower than zero at baseline (BMD P < 0.001 and BMAD P < 0.05) and also after 2 yr treatment (respectively, P < 0.001, P < 0.05, and P < 0.01). Biochemical bone parameters were significantly higher than prepubertal values at baseline, and they decreased during treatment. In conclusion, patients with central precocious and early puberty had normal BMD for chronological age but low BMD for bone age, after 2 yr of treatment with GnRH. Bone turnover decreased during treatment. Changes in body composition resembled those seen in patients with GH deficiency.     

Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group

Near-adult height (AH) was determined in 121 children (72 males and 49 females) with GH deficiency (GHD) who were prepubertal when they began treatment with recombinant DNA-derived preparations of human GH. AH as a SD score was -0.7 +/- 1.2 (mean +/- SD), significantly greater than the pretreatment height SD score (-3.1 +/- 1.2), the predicted AH SD score (-2.2 +/- 1.2; Bayley-Pinneau method), and the height SD score at the start of puberty (-1.9 +/- 1.3). In contrast to studies of GH treatment outcome, which used pituitary-derived GH (pit-GH) in lower doses, we found that males did not have a higher AH SD score than females, spontaneous puberty did not diminish AH, and AH was significantly greater than that predicted at the start of GH treatment. In a multiple regression equation, the statistically significant variables (all P < 0.0001) related to AH (r2 = 0.70) were the following: duration of treatment with GH, sex (males were taller than females, as expected for the normal population), age (younger children had a greater AH) and height at the start of GH, and growth rate during first year of GH. For the AH SD score (r2 = 0.47), pretreatment predicted AH, duration of GH, and bone age delay were significant (P < 0.0002) explanatory variables. Bone age delay (chronological age-bone age) had a negative impact on the AH SD score. Target height, etiology of GHD, previous treatment with pituitary GH, and the presence or absence of spontaneous puberty did not significantly improve the prediction of AH. Early diagnosis of GHD and continuous treatment with larger doses of GH to near AH should improve the outcome in children with short stature due to GHD.     

Growth charts, growth velocity and bone development in childhood obesity

OBJECTIVE: To compare the growth charts of obese subjects (4-18 years) with the Tanner's growth curves and to analyze the growth velocities and bone age of obese children in prepuberty and adolescence. Moreover to compare the relationship between the serum insulinemic and glycemic levels and height standard deviation score (HSDS). DESIGN: Growth charts: this study included 1250 obese subjects (669 males, 581 females) observed between 1981 and 1993 and divided into seven age categories (4-6, 7-8, 9-10, 11-12, 13-14, 15-16, 17-18 years). Growth velocities: yearly growth velocities of 579 obese subjects (325 males, 254 females) were compared to growth velocities of 473 controlled children of the same sex, chronological age and pubertal stage. Bone age (BA) of 846 obese subjects (470 males, 376 females) was estimated. Blood analysis: insulin secretion of 70 obese children was considered and compared to 70 lean controls of equal chronological age and sex. MEASUREMENTS: Growth rate, standardized height and other physical characteristics of the children were measured by trained examiners. All subjects were evaluated singularly for at least 4 years with a follow-up every 6 months. BA was estimated by radiograph of the left hand and wrist using the Tanner-Whitehouse II system by a single observer. For the insulin secretion study and glycemic levels oral glucose tolerance test (OGTT) was performed using a glucose load of 1.75 g/kg per body weight. Plasma insulin was assessed by a double antibody radioimmunoassay. RESULTS: In adipose children the growth charts, referred to 97th centile, 50th centile and 3rd centile, were superior to those of the normal population up to the age of 13 and 12.5 years for male and for female respectively; growth decreases at the above age in both sexes. The obese subjects were equal in height to the non obese subjects as they reached their 18th birthday. The growth velocity (cm/yr) of the obese child, in the age range considered here, does not show differences when compared with the lean child in the prepubertal status (P not significant) but decreases during Tanner's stage II, III IV in boys and girls (P < 0.0001). BA is more advanced over chronological age (delta BA-CA) in both sexes. The increase of BA over CA does not show a remarkable difference during pubertal maturation in boys (P not significant); whereas in girls the delta BA-CA decreases with advancing sexual maturation (P < 0.0001). Our obese subjects have significantly higher plasma insulinemic levels compared with the lean controls (P < 0.0001). Moreover there is a positive correlation between plasma insulinemic levels and HSDS (r = 0.881, P < 0.0001). We did not observe a correlation between serum glycemic levels and HSDS. CONCLUSION: Our data demonstrate that the growth increase in an obese child starts in the first years of life. The statural advantage acquired in the first years of life would be exploited and maintained up to the beginning of puberty and with a growth velocity equal to that of the lean subject. Skeletal maturation is strongly increased in both sexes. Bone age remained advanced during the entire period of pubertal development. During puberty obese subjects demonstrate a less notable growth spurt when compared with lean subjects. The growth advantage gradually decreases and final adult height of obese and normal subjects is equal.     

The effects of thigh soft-tissue stiffness on the control of anterior tibial displacement by functional knee orthoses

BACKGROUND AND OBJECTIVE: Ovarian ultrasonography may be helpful in distinguishing the various types of precocious puberty, and the ovarian appearances increasingly influence choice of therapy in these girls. We examined retrospectively the ovarian volume and prevalence of polycystic ovarian appearance at ultrasound in girls with sexual precocity. DESIGN: Ultrasound examinations were obtained from girls who presented with sexual precocity. If there were several scans from the same individual, the latest was analysed. PATIENTS: The girls were divided into groups: untreated central precocious puberty (n = 25), central precocious puberty treated with GnRH analogue (n = 18) or with GnRH analogue and recombinant human GH (n = 11), girls who had stopped treatment with GnRH analogue and GH (n = 12), premature thelarche and thelarche variant (n = 15) and premature adrenarche (n = 14). MEASUREMENTS: Ovarian volume was calculated and the ovaries were assessed for polycystic appearance using standard criteria. Ovarian volume standard deviation (SD) scores were calculated using means and standard deviations derived from a control population and compared using analysis of variance. Differences from control data were assessed using Student's t-test. RESULTS: Ovarian volume SD scores for all the groups studied were greater than those for control subjects. Girls who had stopped treatment with GnRH analogue and GH had mean ovarian volume of 6.98 ml and ovarian volume SD score (+1.72) greater than that of girls having treatment with GnRH analogue alone (+1.24). Polycystic appearance ovaries were found in 83% of scans in girls who had stopped treatment with GnRH analogue and GH. The ovarian volume SD score of girls with premature adrenarche was less than that of girls with untreated central precocious puberty. CONCLUSIONS: Girls with central precocious puberty had large ovaries which did not return to a volume appropriate for age. Girls treated with GnRH analogue and GH developed very large ovaries when they stopped treatment, and had an increased prevalence of ovaries with a polycystic appearance. Central precocious puberty, or some aspect of its treatment, results in an increased prevalence of polycystic ovarian appearance.     

The status of the gonadotropin releasing hormone test in differential diagnosis of delayed puberty in adolescents over 14 years of age

BACKGROUND: In patients with delayed puberty with a bone age less than 11 years in girls or 12 years in boys, the clinical and endocrinological examination allows the differentiation of patients with the various forms of hypergonadotropic hypogonadism, but not of patients with hypogonadotropic hypogonadism from more prevalent constitutional delay in puberty. Therefore, watchful waiting is generally recommended for differential diagnosis in patients with delayed puberty. On the other hand, the late onset of sexual hormone replacement in patients with hypogonadism will worsen their outcome. PATIENTS AND METHOD: Therefore, we decided to carry out a retrospective study in 105 adolescents who were examined because of short stature or delayed puberty, who were aged 14 to 22 years at first visit and in whom the differential diagnosis of delayed puberty was documented after an at least one-year follow-up in order to find out which endocrinological parameters could have effectively predicted the final diagnosis already at the first visit. RESULTS: Patients with hypogonadotropic hypogonadism differed from patients with constitutional delay in puberty by lower responses of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels to gonadotropin-releasing hormone stimulation (GnRH, 100 micrograms iv) (p < 0.01) as well as by smaller testicular volume (p < 0.05) and by lower testosterone levels (p < 0.01). Stimulated LH < 10 mU/ml differentiated patients with hypogonadotropic hypogonadism from constitutional delay in puberty with a sensitivity of 82% and a specificity of 98%. CONCLUSION: In patients with delayed puberty aged 14 years and older bone age usually exceeds 11 years in girls or 12 years in boys. It thus is in the range, in which normal adult responses of LH to GnRH can be expected. In contrast to patients aged less than 14 years, therefore, measuring GnRH-stimulated LH levels in these patients allows the rapid and effective differential diagnosis of delayed puberty.     

Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone-deficient children

We have followed the growth of stature, sitting height, skinfolds, muscle widths measured radiologically, and skeletal maturity in growth hormone-deficient patients in whom hGH was given and withheld in alternating three-month periods throughout puberty (referred to as "off-hGH" and "on-hGH" periods). Six boys and four girls had true isolated GH deficiency and developed puberty spontaneously. Two boys had gonadotrophin deficiency plus GH deficiency, and five boys had multiple deficiencies; in these boys the signs of puberty were induced by hormone treatment. Boys with true isolated deficiency grew about two-thirds as much in height in the off-hGH periods as in the on-hGH periods; their total gain in height during the adolescent spurt would have been about 20 cm, instead of 30 cm, if hGH had been discontinued at the beginning of puberty. The effect of hGH was entirely on growth in leg-length, however, which virtually ceased during the off-hGH periods. Growth in sitting height altered little when hGH was withdrawn. Growth in limb muscles, however, was GH dependent throughout puberty; during the majority of periods when hGH was withheld, muscle was actually lost; this occurred in the boys who were receiving large doses of testosterone as well as in those producing their own normal amounts. Subcutaneous fat diminished when hGH was given and increased when it was withdrawn; this occurred independently of administration of testosterone. There was little evidence that growth of pubic and axillary hair progressed faster during on-hGH periods, except perhaps in patients with multiple deficiencies. There was some evidence, however, that bone age progressed less rapidly during on-hGH periods than during off-hGH periods in the patients with isolated deficiency. The results in the girls agreed with those in boys so far as stature was concerned, but the relationship with sitting height and leg length appeared to be different; the reasons for this are discussed. We conclude that all children with GH deficiency should continue on treatment with hGH throughout puberty, ideally until growth ceases.     

Reference values for height and weight in Prader-Willi syndrome based on 315 patients

The spontaneous growth of 315 patients (109 girls and 208 boys) with Prader-Willi syndrome (PWS) was analysed in a mixed longitudinal and cross-sectional manner. 33 patients were seen in the department between 1970 and 1994; height and weight of 76 patients from Germany were evaluated by means of a questionnaire with detailed measuring instructions, and 206 definite cases were added from the literature. Mean ( SD) length of newborn babies with PWS was 50.2+/-2.8 cm (145 boys) and 48.9 3.3 cm (79 girls). Mean weight at birth was 2945 570 g in boys and 2782+/-594 g in girls. During the 1st year, the children's growth was nearly normal, thereafter short stature was present in approximately 50% of PWS patients. Between 3 and 13 years of age, the 50th percentile for height in PWS is roughly identical with the 3rd percentile in healthy controls. Body weight was normal for all boys and girls during the first 2 years. Thereafter, a rapid weight gain occurred; after an age of 10 years weight-for-height index in nearly all patients exceeded the normal range. The extent of pubertal growth was reduced for the group. Mean adult height was 161.6+/-8.1 cm (23 males) and 150.2+/-5.5 cm (21 females). Head circumference for age was normal for boys and girls. CONCLUSION: Reference data on spontaneous development of growth and weight gain of children with Prader-Willi syndrome are described allowing a better counselling of patients and parents.     

Biochemical and genetic analysis of variant C of caprine alpha s2-casein (Capra hircus)

Occurrence of any pubertal sign before eight years of age defines premature sexual development but does not always mean precocious puberty (PP); one should distinguish borderline physiological situations which need only a follow-up and frankly pathological situations which need very precise investigations and suitable treatment. The first situations are premature thelarche, pubarche and menarche in which the height and bone maturation, pelvic ultrasonography (US) are normal for age, avoiding hormonal investigations. Conversely in the second situation, the bone age is more advanced than the height age and the pelvic US displays ovarian activity and uterine development. The next step is the characterization of the level of the mechanism of puberty: hypothalamohypophysal or ovarian: in the first case gonadotropin levels are elevated after GnRH infusion, in the second case, depressed. The aetiological diagnosis are in true PP: brain tumors malformations or hamartoma even if negative idiopathic. At ovarian level: ovarian tumors or McCune Albright syndrome or recurrent cysts. The first etiology leads to use GnRH analog in the second the treatment is more delicate.     

Leptin levels in children with central precocious puberty

Several studies have suggested that sufficient serum leptin levels may be involved in the initiation of puberty. To assess further the relationship between leptin and the onset of puberty in humans, we measured the serum leptin concentration in children with central precocious puberty (CPP). We studied 65 children with either idiopathic (IPP; n = 50 girls and 3 boys) or neurogenic central precocious puberty (NPP; n = 5 girls and 7 boys). The serum leptin levels in these patients were compared with normative data from healthy children and adolescents using SD scores that adjust for body mass index (BMI) and Tanner stage. The mean SD scores of IPP and NPP girls were +0.4 +/- 0.1 and +1.0 +/- 0.5, respectively, compared with that of age-matched prepubertal girls and +0.7 +/- 0.2 and +1.6 +/- 0.6 compared with that of girls matched for pubertal stage. The CPP girls with lower BMIs contributed larger SD scores, such that the leptin SD score was negatively correlated with BMI. A similar, modest increase in leptin levels in the CPP girls was evident when additional normative data were considered. The mean leptin SD scores of IPP and NPP boys were -0.9 +/- 0.5 and +0.7 +/- 0.3, respectively, compared with that of normal boys at Tanner stage 3-4. Serum leptin levels in the boys with CPP were not different from those in healthy boys in any of the normative studies. These data should be interpreted cautiously, but they suggest that girls with CPP have modestly elevated serum leptin concentrations compared with those in healthy children and adolescents. In addition, the negative correlation between the leptin SD score and BMI suggests that sufficient leptin levels may be associated with initiation of puberty in girls.     

Psychosocial complications and management of sickle cell disease

Five adolescent girls with Turner syndrome (mean age 13.9 years, mean bone age 12.0 years) were treated with both recombinant human growth hormone (rhGH) and oxandrolone for 2 years with an average increment in height of 13.4 cm. The mean bone age advanced by only 1.2 years, providing an increase in the mean estimated mature height of 9.2 cm. We conclude that rhGH and oxandrolone benefit older teenagers with Turner syndrome because of an increased growth rate with slow progression of skeletal maturation.     

The role of estrogen in bone growth and maturation during childhood and adolescence

Twenty years ago it was believed that pubertal growth was stimulated by testicular androgen in boys and by adrenal androgen in girls. Estrogen, which was used to inhibit growth in excessively tall girls, was not thought to have growth-promoting effects. We hypothesized that estrogen has a biphasic effect on epiphyseal growth, with maximal stimulation at low levels. We showed that the administration of low doses of estrogen, corresponding to a serum estradiol level of about 4 pg/ml (15 pmol/l) caused more than a 60% increase over the prepubertal growth rate in both boys and girls. To test the hypothesis that estrogen is the principal mediator of the pubertal growth spurt in boys, we administered the aromatase inhibitor, testolactone, to boys with familial male-limited precocious puberty. Testolactone produced near normalization of both growth velocity and bone maturation, despite levels of serum testosterone that remained within the adult male range. The observation that low levels of estrogen stimulate growth and bone maturation suggested that estrogen might explain the more rapid epiphyseal maturation of prepubertal girls compared to boys. To determine whether prepubertal girls have higher estrogen levels than prepubertal boys, we developed an ultrasensitive recombinant cell bioassay for estrogen with a sensitivity of 0.02 pg/ml (0.07 pmol/l) estradiol equivalents. Prepubertal girls had approximately eight-fold higher levels of serum estradiol than did prepubertal boys (0.6 +/- 0.6 pg/ml (SD) (2.2 +/- 2.2 pmol/l) vs 0.08 +/- 0.2 pg/ml (0.29 +/- 0.73 pmol/l), P < 0.05). We concluded that the pubertal growth spurt of both sexes is driven primarily by estrogen, and that the more rapid epiphyseal maturation of prepubertal girls (vs boys) may be explained by their higher estradiol levels.     

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.     

Age at onset of puberty following high-dose central nervous system radiation therapy

OBJECTIVE: To determine if a relationship exists between age at irradiation, sex of the patient, and age at onset of puberty and pubarche in children treated with high-dose radiation to the central nervous system. DESIGN: Case series. SETTING: Tertiary care institutional practices and clinics. PATIENTS: Thirty-six children treated with high-dose irradiation (hypothalamic pituitary dose, 30-72 Gy) by conventional (n = 29) or hyperfractionated (n = 7) schedules. Girls were treated before age 8 years and boys before age 9 years. Twenty-six of the 36 children also received chemotherapy. All tumors were distant from the hypothalamic-pituitary region. MAIN OUTCOME MEASURE: Age at onset of puberty and pubarche. RESULTS: In girls, the median age at onset of puberty was 9.3 years vs 10.9 years for controls (P < .01); pubarche occurred at 9.4 years vs 11.2 years for controls (P < .01). In boys, the median age at onset of puberty--genital II--was 11.0 years vs 11.5 years for controls (P = .30); pubarche occurred at a median age of 10.5 years vs 12 years for controls (P = .25). A censored-data normal linear regression model was used to account for children (n = 6) who had not reached puberty. Age at diagnosis (P < .01) and sex (P = .01) were significant predictors of age at onset of puberty. Body mass index SD score (z score) was inversely related to age at onset of puberty (r = -0.77) and was greater at onset of puberty in girls than in boys. CONCLUSION: In children who have received high-dose cranial radiation therapy, a significant positive correlation exists between age at diagnosis and age at onset of puberty in boys and girls.     

Serum concentrations of type I and III procollagen propeptides in healthy children and girls with central precocious puberty during treatment with gonadotropin-releasing hormone analog and cyproterone acetate

Serum levels of type I and III procollagen propeptides (s-PICP and s-PIIINP) were measured in 466 healthy school children and in 23 girls with central precocious puberty (CPP) during GnRH analog and cyproterone acetate therapy, using two commercially available RIAs. In normal children, s-PICP and s-PIIINP changed significantly with age and pubertal development stages. For s-PIIINP, a peak was seen at 12 yr for girls and 13 yr for boys; no peak could be discerned for s-PICP. The prepubertal (Tanner stage 1) s-PICP value (mean +/- SD) for girls was 374 +/- 132 micrograms/L, the midpubertal value (stage 3) was 442 +/- 135 micrograms/L, and the postpubertal value (stage 5) was 203 +/- 103 micrograms/L. The mean s-PIIINP levels for girls were 9.1 +/- 2.4, 15.0 +/- 4.3, and 6.8 +/- 3.1 micrograms/L, respectively. For boys, levels were 362 +/- 119, 544 +/- 138, and 359 +/- 256 micrograms/L for s-PICP and 8.5 +/- 2.2, 14.5 +/- 5.0, and 8.6 +/- 3.8 micrograms/L for s-PIIINP (P < 0.001 for both propeptides in both boys and girls). There was, however, a large variation in normal values for both propeptides within the age groups and pubertal stages. There was a significant correlation of s-PICP and s-PIIINP levels to height velocity in girls (r = 0.35; P < 0.001 and r = 0.33; P < 0.001, respectively), while in boys, only s-PIIINP showed significant correlation to height velocity (r = 0.40; P < 0.001). In untreated girls with CPP, serum levels of s-PIIINP were elevated [PIIINP SD score (SDS), 2.13]. Levels of s-PICP were normal (PICP SDS, 0.39). Levels of both propeptides decreased within 2 months after initiation of therapy and remained below initial values (P < 0.01). The decrease in s-PIIINP after 2 months of therapy showed a significant correlation with the fall in height velocity SDS for chronological age after 6 months of therapy (r = 0.64; P < 0.01). We conclude that s-PIIINP and, to a lesser degree, s-PICP reflect growth in normal children, but due to the large variation, both propeptides seem unsuitable as markers for screening of growth disorders in children.     

Changes in haemoglobin and haematocrit values in children aged 6 to 13 1/2 years in Mexico City

Levels of haemoglobin (Hb), haematocrit (Ht) and mean corpuscular haemoglobin concentration (MCHC) were determined in 523 boys and 350 girls, clinically healthy, ages 6-0 to 13-5 years, middle socio-economic class living in Mexico City. In girls no significant differences according to age were observed in Hb or MCHC; however, Ht was significantly greater at 10-5 than at 10-0 years, without subsequent modifications. In boys, Hb and Ht had a first increase between 10-5 and 11-0 years and a second rise from 12-5 years on: MCHC remained unchanged. Boys were six to twelve months behind girls in regard to Ht increase; however, Ht increased when boys and girls reached similar mean weights (34 kg), heights (138 cm) and surface areas (1-15 m2); concomitantly, they had progressed to stage 2 of sexual development. Clear sex differences began to appear at age 11-5 when boys had higher Hb and Ht values than girls. These data suggest that Hb and Ht changes in these children are not related to chronological age but can be better interpreted if compared to weight, height, surface area or stage of sexual development.