A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. III. The neuroendocrine growth hormone axis during late prepuberty.

Cross-sectional studies demonstrating that physiological GH secretion varies widely among normally and slowly growing children as well as adults have created uncertainty over the definition of normal GH secretion. Furthermore, recent data indicate that the pattern of GH released under identical physiological conditions may be unique for each individual, and suggest that normality may be an individually defined condition. To investigate and develop further this concept and to avoid the confounding effects of fluctuating gonadal steroid hormone levels, we chose as a model normally growing prepubertal boys and performed a longitudinal assessment of spontaneous GH release characteristics (36 24-h GH secretion studies in 9 boys over 9-19 months). Assessment of serum GH pulse characteristics was accomplished using the Cluster pulse detection algorithm. Characteristics of underlying pituitary GH secretory events were estimated by multiple parameter deconvolution analysis. Approximate entropy was used to quantify the serial regularity or orderliness of GH release over 24 h. Among the group data, mean 24-h GH concentrations spanned a range of more than 4-fold (1.6-7.0 micrograms/L). The intersubject coefficient of variation (CV) was 41%. In contrast, values from individuals exhibited much less variability, not only for mean 24-h GH level (CV = 25 +/- 4%; P = < 0.02), but also for all assessed component GH pulse properties (P < 0.01) vs. intersubject values). Similarly, the estimated daily GH production rate, the calculated GH half-lives, and all parameters of GH secretory events varied much less for intraindividual compared to interindividual values. The sizes of the serum GH pulses gave rise to the greatest differences in overall serum GH level among individuals, as demonstrated by the large within-subject CV (50%). The most constant pulse characteristic among subjects was that of 24-h GH pulse frequency (intersubject CV = 30%). Approximate entropy estimates disclosed high within-subject consistency (mean CV = 15%). Several aspects of GH secretion and serum concentrations varied inversely with the subject's mean age-adjusted body mass index, including the 24-h GH production rate (r = -0.67; P < 0.05), the GH secretory burst amplitude (r = -0.73; P = 0.026), the mean serum GH pulse amplitude (r = -0.79; P = 0.011), and the sum of the GH pulse amplitudes (r = -0.66; P = 0.05). By contrast, no consistent pattern of increase or decrease in serum GH concentrations with advancing age was detectable during the prepubertal period. These data suggest that during prepuberty, 1) individual boys regulate daily GH secretion within relatively confined limits characteristic for that individual, much narrower than the range present in the larger population; 2) differences in mean 24-h GH levels among normally growing prepubertal boys arise primarily from differences in GH pulse size; 3) differences in body composition, as indicated by the body mass index, may influence the GH secretion range characteristic of each individual; and 4) there is no consistent change in mean 24-h GH concentrations or the orderliness (approximate entropy) of the GH release process ever time during late prepuberty as the onset of puberty approaches.

A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. II. Estrogen levels as determined by an ultrasensitive bioassay.

A limited number of reports of estrogen levels in prepubertal and early pubertal boys have been published because previous estrogen assays have lacked adequate sensitivity to quantitate circulating estrogen concentrations. Development of a new ultrasensitive assay has permitted measurement of estrogen levels in 23 normally growing boys progressing through puberty. Concentrations were measured at approximately 4-month intervals over a 5- to 8-yr period. The levels increased with maturation in all and correlated directly with chronological age, bone age, weight, height, pubertal stage, and testosterone and insulin-like growth factor-I levels. Of these factors, the level of testosterone had the greatest influence on the estrogen concentration. The time from peak growth velocity also significantly correlated with estrogen level. The estrogen level correlated positively with growth velocity before the time of peak growth velocity and negatively after peak growth velocity. The estrogen levels first increased significantly an average of 3 yr after pubertal onset and reached a peak by 5 yr after pubertal onset. Peak growth velocity was attained an average of 3 yr after pubertal onset. The greatest increase in the rate of rise of the estrogen level was an 11-fold rise during the year in which puberty began. The next most significant increase was a 4.8-fold rise 3 yr after pubertal onset. With respect to pubertal stage, the greatest absolute change occurred from stage 4 to stage 5 and the greatest fold change occurred from stage 1 to stage 2. The estrogen level did not significantly correlate with the 24-h GH level. In conclusion, circulating estrogen levels are very low in all boys prepubertally and rise steadily during adolescent development. The estrogen level is closely related to testosterone concentration and to the time of peak growth velocity. These findings are consistent with the hypothesis that estrogen at low levels augments skeletal growth and maturation in boys (as well as girls). They are also consistent with the hypothesis that continued exposure to estrogen leads to epiphyseal fusion. Further studies are required to define the separate and combined roles of estrogen, GH, and testosterone, as well as other factors, on growth and sexual development at puberty.

A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency--a clinical research center study.

Familial isolated GH deficiency type II (IGHD-II) is an autosomal dominant disorder that has been previously shown in some patients to be caused by heterogeneous GH gene defects that affect GH messenger RNA (mRNA) splicing. We report here our finding of multiple G-->A transitions of the first base of the donor splice site of IVS 3 (+ 1G-->A) in IGHD II subjects from three nonrelated kindreds from Sweden, North America, and South Africa. This + 1G-->A substitution creates an NlaIII site that was used to demonstrate that all affected individuals in all three families were heterozygous for the mutation. To determine the effect of this mutation on GH mRNA processing, HeLa cells were transfected with expression plasmids containing normal or mutant + 1G-->A alleles, and complementary DNAs from the resulting GH mRNAs were sequenced. The mutation was found to destroy the GH IVS 3 donor splice site, causing skipping of exon 3 and loss of the codons for amino acids 32-71 of the mature GH peptide from the mutant GH mRNA. Our finding of exon 3 skipping in transcripts of the + 1G-->A mutant allele is identical to our previous report of a different sixth base transition (+6T-->C) mutation of the IVS 3 donor splice site that also causes IGHD II. Microsatellite analysis of an affected subjects' DNA from each of the three nonrelated kindreds indicates that the + 1G-->A mutation arose independently in each family. Finding that neither grandparent has the mutation in the first family suggests that it arose de novo in that family. Our data indicate that 1) + 1G-->A IVS 3 mutations perturb GH mRNA splicing and cause IGHD II; and 2) these mutations can present as de novo GHD cases.

The use--and misuse--of growth hormone.

Recombinant growth hormone is an effective treatment for many children with short stature, but certainly not for all of them. The approach outlined here will help you make the right choices.

Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy.

Short-term administration of human growth hormone to children with idiopathic short stature can improve mean growth rate and predicted adult height. It is yet unknown whether therapy would alter pubertal development or affect final height. Three-year treatment results in a group of children with idiopathic short stature are reported. For year 1 of the study, 121 prepubertal children were randomly selected to receive somatotropin, 0.3 mg/kg per week, administered subcutaneously three times weekly (n = 63), or to be nontreatment control subjects (n = 58). After 1 year, all subjects were again randomly selected to receive either three-times-weekly or daily dosing at the same total dose. For the 92 subjects who completed 36 months of treatment, mean growth rate increased from a mean of 4.6 cm/yr before treatment to a mean of 8.0 cm/yr in the first year of treatment. Daily dosing resulted in a significantly faster mean growth rate (9.0 cm/yr) than three-times-weekly dosing (7.8 cm/yr) (p = 0.0005). Mean growth rates were 7.6 and 7.2 cm/yr during years 2 and 3, respectively, and did not differ by dosing group. Mean standardized height for all subjects improved from -2.7 to -1.6 after 3 years. When the growth rate was standardized for bone age, however, subjects who remained prepubertal had a significantly greater gain in mean height SD score than subjects who became pubertal during that 3-year period (p < 0.02). Mean standardized Bayley-Pinneau predicted adult height SD score increased from -2.7 to -1.6 and was independent of the timing of pubertal onset, but for individuals this score was more variable. Year-1 growth response, expressed as growth rate or change in height SD score, was the best predictor of growth in subsequent years. Responses to therapy could not be reliably predicted from baseline anthropometric variables, plasma insulin-like growth factor I SD score, growth hormone levels. Final height assessment will be needed to determine the ultimate benefit of therapy.

A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. I. Serum growth hormone-binding protein.

Previous studies have provided compelling evidence that GH secretion increases transiently during midpuberty in normally growing children. Although it is likely that the increase in GH production serves a primary role in generating the pubertal growth spurt, such a conclusion necessarily assumes that other essential "down-stream" components of the GH axis responsible for mediating the effects of GH remain unchanged. To investigate this concept, we assessed longitudinally another important component of the endogenous GH axis, the serum GH-binding protein (GHBP)/receptor system, in a cohort of 11 normal boys as they matured through normal puberty. At 4-month intervals over 4.0-5.1 yr, 24-h serum GH concentration profiles and serum GHBP activity were evaluated. Serum GHBP levels varied over a more than 12-fold range (40-504 pmol/L) among all subjects. However, the values for individual subjects consistently varied within more narrow limits. The coefficient of variation for values from all subjects was 51% compared to the mean intrasubject coefficient of variation of only 30% (P < 0.05). Although the highest GHBP level (all subjects) was 12.6-fold greater than the lowest, the mean intrasubject range was only 3.1 +/- 0.5-fold (P < 0.05). The overall mean serum GHBP level correlated directly with the overall mean body mass index (r = 0.69; P = 0.018), but correlated inversely with the mean 24-h GH concentration (r = -0.61; P < 0.05). There was no significant increase in the GHBP level during puberty. However, because mean 24-h GH concentrations did increase during midpuberty, the data suggest that an increase in the relative amounts of free vs. bound GH develops during the period of the pubertal growth spurt. These data indicate that serum GHBP levels are regulated in individual children within much more narrow limits than those present in the larger population and do not undergo the dramatic changes during puberty typical of GH secretion and linear growth velocity. As a consequence, alterations may develop in the relative amounts of free vs. bound GH present in serum during the midpubertal years compared to those present during either the prepubertal or postpubertal periods. The majority of the known age-related increase in serum GHBP levels probably occurs before the period of active pubertal development. These findings strengthen further the concept that the midpubertal changes in GH secretion serve a primary role in generating the growth spurt.(ABSTRACT TRUNCATED AT 400 WORDS)

Altered growth hormone secretory dynamics in prepubertal males with constitutional delay of growth.

We have used the technique of deconvolution analysis to determine if abnormalities in growth hormone (GH) secretion or metabolic clearance underlie the observed alterations in circulating hormone concentrations in a group of seven prepubertal males with constitutional delay of growth (SHORT-DBA). The results were compared with data obtained from 13 healthy, short prepubertal males (SHORT) and 11 healthy prepubertal male subjects of normal stature (NORMAL). Although the mean 12-h overnight GH production rates were invariant among the groups (8.0 +/- 1.0 versus 7.3 +/- 0.7 versus 6.7 +/- 1.2 micrograms/L, NORMAL versus SHORT versus SHORT-DBA for all comparisons), different secretory mechanisms were operative. The secretory burst half-duration (time interval of the secretory event at half-maximal amplitude) of the SHORT-DBA subjects (26 +/- 1 min) was greater (p = 0.02) than that of the SHORT group (20 +/- 1 min); values for both the SHORT and SHORT-DBA subjects were indistinguishable from that of NORMAL controls (22 +/- 2). Both the mass of GH released per secretory episode and the maximal rate of hormone secretion were less (p < or = 0.02 and the p < 0.01, respectively) for the SHORT-DBA subjects [16 +/- 2 micrograms/unit of body distribution volume (Lv) and 0.6 +/- 0.1 microgram/Lv/min, respectively] compared with those of the NORMAL (26 +/- 2 micrograms/L, and 1.1 +/- 0.1 micrograms/Lv/min, respectively) and SHORT (28 +/- 4 micrograms/Lv and 1.3 +/- 0.2 micrograms/Lv/min, respectively) groups; values for the latter two groups were indistinguishable.(ABSTRACT TRUNCATED AT 250 WORDS)

Ovulation and menstrual function of adolescent girls with central precocious puberty after therapy with gonadotropin-releasing hormone agonists.

Chronic GmRH agonist (GnRHa) administration has been shown to suppress pituitary-gonadal function in children with central precocious puberty (CPP), but long term data after the reactivation of gonadarche posttherapy are not yet available. This study evaluated the menstrual function of 46 girls with CPP who had been treated for at least 2 yr with GnRHa (deslorelin or histrelin, sc, daily) and were up to 7 yr posttreatment, including 21 postmenarcheal girls who collected weekly overnight urine samples for 12 consecutive weeks to assess rates of ovulation by urinary pregnanediol-3 beta-glucuronide measurements. Menarche occurred at age 12.1 +/- 1.0 yr (mean +/- SD), on the average 1.2 +/- 0.8 yr posttherapy (range, 0.1-4.3 yr). Menstrual cycle lengths became increasingly regular, with cycles of 25- to 35-day duration reported by 41% of the girls in the first year postmenarche and 65% of the girls studied 3 or more years postmenarche. Ovulation was demonstrated in 50% of the girls studied within 1 yr of menarche and in 90% of the girls studied 2 yr or more postmenarche, including 5 girls who reported pregnancies. The development of regular ovulatory menstrual function in these girls with CPP is in accord with previously documented patterns in normal adolescents. While these data provide further evidence supporting the safety of long term GnRHa therapy, continued studies will be necessary to characterize fully the reproductive function in CPP patients through adolescence and adulthood.

Psychosocial short stature: a syndrome with many variables.

PSS is at least two syndromes of significant frequency, which often go unrecognized. It occurs in all socioeconomic groups. It is variable in its presentation and often masquerades in its subtle forms as other pathological causes of short stature such as GHD, CDGP, malabsorption and failure to thrive. It is an entity about which we understand little in respect to biochemical pathophysiology, and one which offers a challenge to both clinicians and basic scientists.

Properties of spontaneous growth hormone secretory bursts and half-life of endogenous growth hormone in boys with idiopathic short stature. Genentech Collaborative Group.

We analyzed endogenous GH secretory dynamics and MCRs by a novel quantitative deconvolution technique in 20 boys with idiopathic short stature (ISS) and 35 boys of normal stature in Tanner stage I of puberty. We tested the null hypotheses that 1) ISS is not associated with any alterations in the frequency, mass, amplitude, or duration of spontaneous GH secretory bursts and/or the 24-h GH production rate; and 2) the half-life of endogenous GH is not altered in ISS. The boys with ISS had a mean (+/- SEM) bone age of 8.0 +/- 0.42 yr and a chronological age of 10 +/- 0.50 yr. The latter was similar to the chronological (and bone) age of the normal boys of 9.8 +/- 0.23 (and 9.3 +/- 0.34) yr. Mean height SD scores were significantly lower in ISS boys, viz. -2.7 +/- 0.15 in ISS vs. +0.34 +/- 0.13 in normal boys (P less than 0.001). Plasma insulin-like growth factor-I concentrations were similar in the two groups, as were (24-h) mean serum GH concentrations, viz. 3.5 +/- 0.29 micrograms/L in ISS and 4.1 +/- 0.49 micrograms/L in normal boys (P = NS). Deconvolution analysis revealed that the mean number of GH secretory events per 24 h was similar in normal and ISS boys, viz. 9.6 +/- 0.76 (normal) vs. 8.4 +/- 0.55 (ISS), and that there was no significant difference in mean GH interburst intervals. The amplitude, mass, and duration of computer-resolved GH secretory bursts also did not differ in normal and ISS boys. The half-lives of endogenous GH were estimated to be 16 +/- 0.77 min in the ISS and 18 +/- 0.93 min in the control boys (P = NS). The calculated daily GH secretion rate per unit distribution volume was not significantly reduced in ISS, i.e. 194 +/- 19 micrograms/L.day in ISS vs. 177 +/- 19 micrograms/L.day in control boys. Moreover, daily GH secretion rates corrected for body mass index (weight/height2) in the twp groups were not significantly different. In summary, the present cohort of boys with ISS manifested no significant alterations in GH secretory burst frequency, duration, mass, or amplitude or in the half-life of endogenous GH compared to normal boys in Tanner stage I of pubertal development. Indeed, whether daily GH secretion rates are expressed per unit distribution volume or per unit body mass index, groups of boys with ISS and normal height controls secrete similar total amounts of GH. We conclude that the overall dynamics of GH secretion and clearance in boys with ISS considered as a whole cannot be distinguished readily from physiological patterns observed in prepubertal boys of normal height.

Endogenous growth hormone secretion and clearance rates in normal boys, as determined by deconvolution analysis: relationship to age, pubertal status, and body mass.

Mean plasma GH concentrations increase in normal boys during mid- to late-puberty. To investigate the nature of the pituitary secretory events and/or altered metabolic clearance responsible for these serum GH concentration changes, we performed multiple-parameter deconvolution analysis of 46 24-h serum GH concentration-time series obtained from normal boys at various stages of puberty and young adulthood. The subjects ranged in chronological age from 7-27 yr. The height and weight of each subject were between the 5th and 95th percentile for age. The calculated daily mass of GH secreted was greatest (P less than 0.001) in late pubertal boys (mean +/- SE, 1810 +/- 250 micrograms/24 h) and was triple the value in prepubertal boys (610 +/- 65 micrograms/24 h). When the values were normalized and expressed as mass of GH secreted per unit (m2) body surface area or per L distribution volume, GH secretion in late pubertal boys was still significantly greater than that in any other group (P less than 0.05). These values for late pubertal boys were nearly double the corresponding values for prepubertal boys (1160 +/- 160 vs. 600 +/- 58 micrograms GH/m2.24 h and 440 +/- 63 vs. 270 +/- 25 micrograms GH/L vol.24 h, respectively). When the effect of clearance mechanics on serum GH concentrations was removed mathematically, the primary change in predicted GH secretory burst parameters during pubertal development was an increase in GH mass released per burst resulting from an increase in the maximal rate of GH secretion attained within the bursts. These changes in the amplitude of GH release events were specific, in that they were largely independent of any accompanying alterations in duration or frequency of the GH secretory bursts or in serum GH half-life. Correlation analysis revealed that the 24-h GH secretion rate varied inversely with the subjects' body mass index SD score (r = -0.65; P less than 0.01), suggesting that differences in body mass, even within the normal range, contribute to the wide variability in daily GH secretion rates among normally growing children. The plasma insulin-like growth factor-I concentrations of all subjects correlated positively with the calculated 24-h GH secretion rate (r = 0.51; P less than 0.001). In summary, the primary neuroendocrine alteration responsible for the augmented serum GH concentrations characterizing mid- to late-puberty in boys is an increased mass of GH released per pituitary secretory episode resulting from an increased maximal rate of GH secretion within each burst.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone-binding protein activity is inversely related to 24-hour growth hormone release in normal boys.

To investigate the physiological relationship between serum GH-binding proteins and 24-h GH release, we compared the 24-h GH pulse attributes in serum samples obtained at 20-min intervals to the serum GH-binding protein activity (GH-BP) from 38 normal boys between 7 5/12 and 18 4/12 yr of age. GH-BP was determined in a serum sample from each study (containing less than 1.0 micrograms/L GH) using a standardized GH-BP assay. GH-BP results are expressed as the percentage of [125I]human GH bound to the high affinity GH-BP complex (peak II) per 160 microL serum. There were significant inverse relationships between the high affinity (receptor-related) GH-BP and several characteristics of 24-h GH release. Specifically, GH-BP was significantly (P less than 0.005 for all), but negatively, correlated with mean 24-h GH concentration (r = -0.62), sum of the GH pulse amplitudes (r = -0.57), sum of the GH pulse areas (r = -0.55), interpulse mean GH concentration (r = -0.53), and number of GH pulses per 24 h (r = -0.53). In addition, GH-BP correlated positively with the mean time interval between pulses (r = 0.59). There was also a significant positive correlation (r = 0.75; P less than 0.001) between GH-BP and the subject's age-adjusted body mass index SD score (BMI-SDS). Each characteristic of 24-h GH release correlating inversely with GH-BP also correlated inversely with BMI-SDS (P less than 0.01 for all comparisons). GH-BP did not, however, correlate with plasma insulin-like growth factor-I levels, serum testosterone concentrations, or height SDS. Binding to the low affinity GH-BP (peak I) did not correlate significantly with any of the examined GH pulse attributes, BMI-SDS, or the degree of binding to the high affinity GH-BP (peak II). We conclude that an inverse relationship exists between the high affinity serum GH-BP and 24-h GH release in boys under normal physiological conditions. We speculate that abnormalities in this relationship probably also exist and may underlie some disorders of growth.

Testosterone and oxandrolone, a nonaromatizable androgen, specifically amplify the mass and rate of growth hormone (GH) secreted per burst without altering GH secretory burst duration or frequency or the GH half-life.

We investigated the mechanisms by which androgens increase mean circulating GH concentrations in boys. We tested two hypotheses: 1) testosterone increases serum GH concentrations at least in part via an androgen receptor-mediated mechanism, rather than exclusively by way of aromatization to estrogen; 2) androgen augments one or more specific features to GH secretion (secretory burst number, amplitude, and/or duration) and/or prolongs the half-life of GH removal. To examine these hypotheses, prepubertal boys with constitutionally delayed development and/or growth were given injections of testosterone (100 mg monthly; n = 7) or treated with oral oxandrolone, a nonaromatizable androgen (1.25 mg twice daily; n = 5). Pulsatile GH release was studied before and during androgen administration by sampling blood at 20-min intervals for 24 h. The immunoreactive GH time series were subjected to a novel deconvolution technique, which revealed that 1) testosterone and oxandrolone each increased mean (24-h) serum GH concentrations significantly; 2) both androgens augmented the daily endogenous GH secretory rate significantly; 3) increased GH production resulted from a higher mass of GH secreted per burst and a higher maximal rate of GH secretion within each burst; and 4) androgens amplified the magnitude of the nyctohemeral rhythm in the mass (but not frequency) of GH secretory pulses. The observed effects of androgen were specific, since the number and duration of GH secretory bursts and the subject-specific GH half-life were unaltered by androgen treatment. We conclude that androgen acting apart from conversion to estrogen is capable of specifically activating the somatotropic axis via distinct neuroendocrine secretory mechanisms.

Sleep modulation of neuroendocrine function: developmental changes in gonadotropin-releasing hormone secretion during sexual maturation.

To assess sleep-associated changes in gonadotropin-releasing hormone secretion during sexual maturation, we studied nighttime and daytime patterns of LH and FSH secretion in two groups with qualitatively similar sex steroid levels: girls with central precocious puberty and young adult women in the early follicular phase of an ovulatory menstrual cycle. In the girls with central precocious puberty, all indices of LH secretion were significantly higher at night than during the day (mean LH levels, 12 +/- 2 versus 5 +/- 1 IU/L, p less than or equal to 0.01; LH pulse amplitude 16 +/- 2 versus 7 +/- 1 IU/L, p less than or equal to 0.01; and LH pulse frequency 0.70 +/- 0.05 versus 0.35 +/- 0.08 pulse/patient-h, p less than or equal to 0.01). Girls with a history of menses, who were presumably the most mature, lacked this diurnal variability. Mean nocturnal FSH levels were only slightly higher than daytime levels (7.6 +/- 0.5 versus 7.2 +/- 0.5 IU/L, p less than or equal to 0.05) resulting in alternating periods of LH (nighttime) and FSH (daytime) predominance in this pubertal population.(ABSTRACT TRUNCATED AT 250 WORDS)

Variations of pulsatile growth hormone release in healthy short prepubertal boys.

Overnight growth hormone (GH) concentrations obtained by frequent venous sampling of 20 healthy, short prepubertal boys were evaluated using the objective pulse detection algorithm, CLUSTER. The resulting pulsatile characteristics were compared with those of 11 healthy prepubertal boys of normal stature and with those of nine prepubertal children with documented GH deficiency. Although no significant differences of pulsatile GH release were found between the normal and short subjects, a subset of the short prepubertal boys with significantly delayed skeletal ages had subnormal sum of GH pulse areas and sum of GH pulse amplitudes. The finding of a significant correlation in all subjects between growth velocity and the sum of GH pulse amplitudes is important, as the results are compatible with the hypothesis that alterations of amplitude-modulated GH release underlie the pathophysiology of suboptimal growth in some short prepubertal children.

Gonadotrophin-releasing hormone agonist treatment of central precocious puberty: an analysis of growth data in a developmental context.

Growth and skeletal maturation was assessed in 83 girls with central precocious puberty (CPP) during pituitary-gonadal suppression induced by treatment with a gonadotrophin-releasing hormone agonist (GnRHa). The mean pretreatment chronological age (CA) was 6.3 years and the mean bone age (BA) was 10.6 years. During the suppression of gonadal sex steroid secretion, mean height velocity (HV) decreased from a pretreatment value of 10.8 cm/year to 5.9 (year 1, n = 83), 4.9 (year 2, n = 72), 4.2 (year 3, n = 45), and 4.4 (year 4, n = 23) cm/year. During each interval, there was a negative correlation between HV and the pretreatment BA. In addition, the rate of skeletal maturation was reduced during GnRHa treatment (delta BA/delta CA = 0.6 +/- 0.1 over 3 years, n = 45). The rate of skeletal maturation during therapy was also negatively correlated with pretreatment BA. Predicted adult stature, based upon zeta-scores of height for BA, increased significantly and progressively during therapy but the changes in height SDS for BA varied significantly. Since HV, delta BA/delta CA, and the change in height SDS for BA (delta HT SDS for BA) during pituitary-gonadal suppression all correlated with the initial degree of skeletal maturation, the effect of GnRHa therapy on final adult height in children with CPP will be best understood if growth data are assessed within a developmental framework.

Long-term follow-up of hypopituitary patients treated with human growth hormone.

Thirty-six former human growth hormone (hGH) recipients underwent comprehensive physical, endocrine and lipoprotein evaluations as adults. Treatment was associated with a decrease in height standard deviation score (SDS) in males from 4.0 pretreatment to 2.1 as adults, and in females from 4.2 to 2.5. Males showed a better growth response to treatment than did females. Plasma somatomedin-C levels were subnormal in 30 patients, but were higher in isolated growth-hormone-deficient patients than in others. Three men and 1 woman showed evidence suggesting a disturbance in pulsatile gonadotropin release despite the previous documentation of normal serum gonadotropin levels. Hypertriglyceridemia was not observed, and the women's plasma cholesterol levels were unremarkable. Men, however, showed higher-than-expected total cholesterol, LDL-cholesterol, and HDL-cholesterol concentrations. The last finding may explain the lack of increased cardiovascular morbidity in this group.