PubMed Health⌕ Search

Biomedical subjects

R M Blizzard

Publications and source records attributed to R M Blizzard.

At least 19 recordsLinked to original sources
PubMed1992

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.

Adolescent↗
PubMed1992

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)

Adolescent↗
PubMed1992

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.

Adolescent↗
PubMed1992

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.

Child↗
PubMed1991

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.

Adolescent↗
PubMed1990

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.

Adolescent↗
PubMed1990

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.

Age Factors↗
PubMed1990

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.

Adolescent↗
PubMed1990

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)

Adolescent↗
PubMed1990

Atenolol enhances nocturnal growth hormone (GH) release in GH-deficient children during long term GH-releasing hormone therapy.

The effect of the selective beta 1-adrenergic blocking agent atenolol (50 or 100 mg, orally) on spontaneous and GH-releasing hormone (GHRH)-stimulated GH release was evaluated in six GH-deficient children during long term therapy with GHRH. Nocturnal GH concentrations were determined every 20 min for 12 h under the following four conditions: 1) control, 2) atenolol administration only, 3) sc GHRH administration only, and 4) combined GHRH and atenolol administration. The mean 12-h nocturnal GH concentrations after administration of atenolol alone [2.4 +/- 0.6 microgram/L (mean +/- SEM)] or GHRH alone (2.7 +/- 1.0 micrograms/L) were indistinguishable from baseline values (2.0 +/- 0.5 microgram/L; P greater than 0.05). In contrast, the addition of atenolol to ongoing GHRH therapy caused a clear augmentation of 12-h overnight GH release compared to that during all other study periods (5.0 +/- 1.3 micrograms/L; P less than 0.05). In a subset of three subjects for whom GH pulse characteristics were determined, the primary mode of the enhanced GH release was through an increase in the amplitude of serum GH pulses. These results are consistent with the hypothesis that beta-adrenergic blocking compounds enhance the responsivity of the pituitary gland to agents that permit GH release by inhibiting hypothalamic somatostatin secretion or action. They suggest that atenolol may have potential as an adjunctive therapy in some children with abnormalities of GH secretion when GHRH is the primary therapeutic agent.

Age Determination by Skeleton↗
PubMed1990

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.

Adolescent↗
PubMed1989

Treatment of the young child with postoperative central diabetes insipidus.

A continuous intravenous infusion of aqueous vasopressin (dosage range, 1.0 to 3.0 mU/kg/h) was administered to two patients (respective ages, 2 weeks and 3 years 1 month) who had postoperative central diabetes insipidus to determine if this mode of therapy is helpful in the very young patient. In both patients the polyuria and serum hyperosmolality were corrected. These findings suggest that an intravenous infusion of aqueous vasopressin can provide satisfactory control of the polyuria and electrolyte disturbances found in young children with acute postoperative central diabetes insipidus.

Brain↗
PubMed1989

Pathophysiological features of the pulsatile secretion of biologically active luteinizing hormone in man.

The development of an in vitro bioassay of high specificity, sensitivity and precision for the measurement of low circulating concentrations of biologically active glycoprotein hormones has offered exciting new insights into the in vivo secretion and metabolic clearance of luteinizing hormone (LH) in various pathophysiological states. Moreover, the most recent combined application of the rat interstitial cell testosterone (RICT) bioassay and a novel multiple-parameter deonvolution model has allowed investigators to dissect plasma concentration profiles of bioactive LH into defined secretory bursts, which have numerically explicit amplitudes, locations in time, and durations, and are acted upon by determinable subject- and study-specific endogenous metabolic clearance rates. Here, we have: (i) reviewed the ability of the endogenous GnRH pulse signal to regulate the in vivo secretion of biologically active LH molecules as assessed in the RICT and by deconvolution mechanics; (ii) demonstrated that low-dose exogenous GnRH pulses effectively mimic spontaneous bioactive LH pulsatility; (iii) investigated the role of endogenous androgen and estrogen in modulating bioactive gonadotropin secretion in men and women; and (iv) described significant alterations in endogenous LH bioactivity in puberty and healthy aging.

Aging↗
PubMed1989

Androgen-dependent somatotroph function in a hypogonadal adolescent male: evidence for control of exogenous androgens on growth hormone release.

A 14(10/12)-year-old white male with primary gonadal failure following testicular irradiation for acute lymphocytic leukemia was evaluated for poor growth. He had received 2400 rad of prophylactic cranial irradiation. The growth velocity had decelerated from 7 to 3.2 cm/yr over 3 years. His bone age was 12(0/12) years (by TW2-RUS), and his peak growth hormone (GH) response to provocative stimuli was 1.4 ng/mL. The 24-hour GH secretion was studied by drawing blood every 20 minutes for 24 hours. The resulting GH profile was analyzed by a computerized pulse detection algorithm, CLUSTER. Timed serum GH samples were also obtained after a 1 microgram/kg IV bolus injection of the GH releasing factor (GRH). The studies showed a flat 24-hour profile and a peak GH response to GRH of 3.9 ng/ml. Testosterone enanthate treatment was started, 100 mg IM every 4 weeks. Ten months after the initiation of therapy the calculated growth rate was 8.6 cm/yr. The 24-hour GH study and GRH responses were repeated at the time, showing a remarkably normal 24-hour GH secretory pattern and a peak GH response to GRH of 14.4 ng/mL. Testosterone therapy was discontinued, and 4 months later similar studies were repeated. A marked decrease in the mean 24-hour GH secretion and mean peak height occurred, but with maintenance of the GH pulse frequency. The GH response to GRH was intermediate, with a peak of 8 ng/mL. There was no further growth during those 4 months despite open epiphyses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys.

To investigate the mechanisms subserving physiological alterations in circulating GH concentrations during puberty, we assessed the GH pulse characteristics of 60 24-h serum GH profiles obtained from healthy male volunteers of normal stature (aged 7-27 yr) whose physical development spanned the entire pubertal range. Subjects were divided into five study groups based on degree of sexual maturation. The mean 24-h concentration of GH was greater in late pubertal boys than in all other groups (P less than 0.001). This elevation primarily reflected a greater size, rather than number, of GH pulses, whether assessed as mean GH pulse area (P = 0.004 vs. all other groups), mean GH pulse amplitude (P = 0.001), or sum of the GH pulse areas (P less than 0.001). GH pulse frequency was indistinguishable among all groups (P greater than 0.05). However, circadian GH rhythms varied significantly in amplitude and mean values (but not in phase) throughout puberty. Plasma insulin-like growth factor-I levels were greatest in the late pubertal boys (1.98 +/- 0.15 U/mL) and remained elevated in the postpubertal group (1.44 +/- 0.18). The mean value for the adult men (0.74 +/- 0.06) was indistinguishable from that of prepubertal boys (0.90 +/- 0.13). In addition, all assessed characteristics of GH pulses and circadian rhythms in adults were equal to or less than corresponding values in prepubertal boys. We conclude that circulating GH concentrations transiently increase during mid- to late puberty in normal boys, primarily through augmentation of the size of GH pulses, but return to or below prepubertal levels during early adulthood.

Adolescent↗
PubMed1989

Changes in growth hormone (GH) secretion and in growth during puberty.

During normal adolescent development in males testosterone induces the adolescent growth spurt, at least in part, by increasing GH production via an increase in the amplitude of the peaks of GH which are released, and not by increasing the frequency of GH pulses. Testosterone and estrogen administration at low or modest doses to individuals with the capacity to produce GH causes GH production and IGF-I levels to increase. Testosterone given to GHD patients does not increase either of these factors. In addition, there may be two actions for growth promotion by testosterone. One unequivocally results from an increase in GH production in the presence of low or modest levels of testosterone. A direct action on bone growth is probably present also, as reflected by the growth promoting effect of oxandrolone, a weak androgen, in boys with CDGA in the absence of increased GH production.

Adolescent↗