Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2015; 100 (6): 2354-2363
The histrelin implant has proven to be an effective method of delivering GnRH analog (GnRHa) therapy to children with central precocious puberty (CPP), yet there are limited data available regarding hormonal suppression and auxological changes during an extended course of therapy.This was a phase 3, prospective, open-label study.Thirty-six children with CPP who participated in a phase 3, open-label study and required further GnRHa therapy were eligible to continue treatment receiving a new implant upon removal of the prior 12-month histrelin implant during a long-term extension phase.Hormone levels and auxologic parameters were measured periodically for up to 6 years of treatment and up to 1 year of posttreatment follow-up.Hormonal suppression was maintained throughout the study in patients who had prior GnRHa therapy (n = 16) and in treatment-naive patients (n = 20). Bone age to chronological age ratio decreased from 1.417 (n = 20) at baseline to 1.18 (n = 8) at 48 months in treatment-naive children (P < .01). Predicted adult height in girls increased from 151.9 cm at baseline to 166.5 cm at month 60 (n = 6; P < .05), with a 10.7-cm height gain observed among treatment-naive children (n = 5). No adverse effect on growth or recovery of the hypothalamic-pituitary-gonadal axis was observed with hormonal suppression. The histrelin implant was generally well tolerated during long-term therapy.Long-term histrelin implant therapy provided sustained gonadotropin suppression safely and effectively and improved predicted adult height in children with CPP.
View details for DOI 10.1210/jc.2014-3031
View details for Web of Science ID 000360840000049
View details for PubMedID 25803268
Letrozole vs Anastrozole for Height Augmentation in Short Pubertal Males: First Year Data JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2014; 99 (11): 4086-4093
Aromatase inhibitors are used off-label to treat short stature in peripubertal boys.To investigate short- and long-term hormonal and auxologic differences in short pubertal boys treated with letrozole (L) or anastrozole (A).PATIENTS are seen for laboratory evaluation and physical examination every 6 months, bone age yearly, DEXA and spine film every 2 years. They will be followed until they reach their final height. This is a preliminary report after 1 year of treatment.A single academic children's hospital outpatient clinic.Boys with age >10 years, bone age 14 years, clinical and hormonal evidence of central puberty, and either height < fifth percentile or predicted adult height (PAH) more than 10 cm below mid-parental height (MPH).Letrozole (2.5 mg) or anastrozole (1 mg) was administered orally each day.Hormonal and clinical parameters, growth velocity, and change in bone age and PAH.Thirty-nine boys have completed 1 year of treatment. Baseline means were age 14.1 years, PAH 166 cm, and testosterone 198 ng/dL. At 1 year, letrozole resulted in higher LH (L 6.1 2.5 vs A 3.2 1.7 IU/L) and testosterone (1038 348 vs 536 216 ng/dL) with lower estradiol (2.8 2.8 vs 5.6 2.9 pg/mL) and IGF-1 (237 51 vs 331 79 ng/mL). First year growth velocities were identical (7.2 cm/year), but an increase in PAH was greater in the anastrozole group (4.2 3.5 vs 1.4 4.4 cm, p = 0.03) after 1 year.We present first-year data from a direct comparison of anastrozole and letrozole for height augmentation in short pubertal boys. Letrozole was more potent in hormonal manipulation than anastrozole. First-year growth velocities were comparable, but improvement in PAH was greater in the anastrozole group. It remains to be seen if positive PAH trends will translate to increase in final height in either group.
View details for DOI 10.1210/jc.2014-2432
View details for Web of Science ID 000346743100023
Precocious puberty CURRENT OPINION IN OBSTETRICS & GYNECOLOGY 2014; 26 (5): 332-338
Precocious puberty continues to elicit great interest and concern among medical practitioners, as well as the public.Studies have elucidated neural regulation of puberty by kisspeptin, neurokinin B, and other factors. Cohort studies from the North America and Europe suggest that the age of thelarche may be earlier than determined 2 decades ago, and menarche may be slightly earlier, but the causes are unclear. Long-term outcomes of gonadotropin-releasing hormone analog therapy demonstrate increases in final height in the youngest treated patients, with no apparent adverse bone or reproductive consequences.Although the appropriate threshold age of onset of central puberty remains uncertain, gonadotropin-releasing hormone analog therapy is well tolerated and effective in suppressing luteinizing hormone pulses and ovarian activity.
View details for DOI 10.1097/GCO.0000000000000099
View details for Web of Science ID 000341836200002
View details for PubMedID 25144596
Review of Outcomes After Cessation of Gonadotropin-releasing Hormone Agonist Treatment of Girls with Precocious Puberty PEDIATRIC ENDOCRINOLOGY REVIEWS PER 2014; 11 (3): 306-317
Review of outcomes after cessation of gonadotropin-releasing hormone agonist treatment of girls with precocious puberty. Pediatric endocrinology reviews : PER 2014; 11 (3): 306-317
Although gonadotropin-releasing hormone agonists (GnRHa) have been the standard of care of central precocious puberty (CPP) management for many years, there are still questions about the long-term consequences of treatment. With increased utilization of GnRHa treatment, it is now possible to assess posttreatment outcomes in the immediate posttreatment period and into adulthood. This literature review reports on the long-term effects of GnRHa therapy in girls with CPP after therapy has been discontinued. Published reports confirm the reversibility of hypothalamic-pituitary-ovarian axis suppression in females after cessation of GnRHa therapy, with the majority of patients achieving ovulatory menstrual cycles of normal timing and duration. GnRHa therapy does not appear to induce polycystic ovary syndrome or have long-term negative repercussions on either bone mineral density or body composition. Evidence is currently insufficient to identify agent-specific differences in outcomes, reproductive function, and health of offspring.
View details for PubMedID 24719967
A randomized trial of transdermal and oral estrogen therapy in adolescent girls with hypogonadism. International journal of pediatric endocrinology 2014; 2014 (1): 12-?
Adolescent females with ovarian failure require estrogen therapy for induction of puberty and other important physiologic effects. Currently, health care providers have varying practices without evidence-based standards, thus investigating potential differences between oral and transdermal preparations is essential. The purpose of this study was to compare the differential effects of treatment with oral conjugated equine estrogen (OCEE), oral 17 estradiol (OBE), or transdermal 17 estradiol (TBE) on biochemical profiles and feminization in girls with ovarian failure.20 prepubertal adolescent females with ovarian failure, ages 12-18 years, were randomized to OCEE (n=8), OBE (n=7), or TBE (n=5) for 24months. Estrogen replacement was initiated at a low dose (0.15mg OCEE, 0.25mg OBE, or 0.0125mg TBE) and doubled every 6months to a maximum dose of 0.625mg/d OCEE, 1mg/d OBE, or 0.05mg/d TBE. At 18months, micronized progesterone was added to induce menstrual cycles. Biochemical markers including sex hormones, inflammatory markers, liver enzymes, coagulation factors, and lipids were obtained at baseline and 6month intervals. Differences in levels of treatment parameters between the groups were evaluated with one-way analysis of variance (ANOVA). The effect of progesterone on biochemical markers was evaluated with the paired t-test.Mean (SE) estradiol levels at maximum estrogen dose (18months) were higher in the TBE group (5319pg/mL) compared to OCEE (145pg/mL) and OBE (125pg/mL) (p0.01). The TBE and OBE groups had more effective feminization (100% Tanner 3 breast stage at 18months). There were no statistical differences in other biochemical markers between treatment groups at 18months or after the introduction of progesterone.Treatment with transdermal 17 estradiol resulted in higher estradiol levels and more effective feminization compared to oral conjugated equine estrogen but did not result in an otherwise different biochemical profile in this limited number of heterogeneous patients. OBE and TBE provide safe and effective alternatives to OCEE to induce puberty in girls, but larger prospective randomized trials are required.NCT01023178.
View details for DOI 10.1186/1687-9856-2014-12
View details for PubMedID 24982681
Random unstimulated pediatric luteinizing hormone levels are not reliable in the assessment of pubertal suppression during histrelin implant therapy. International journal of pediatric endocrinology 2013; 2013 (1): 20-?
Gonadotropin-releasing hormone agonist (GnRHa)-stimulated luteinizing hormone (LH) is the standard hormonal assessment for both diagnosis and therapeutic monitoring of children with central precocious puberty (CPP). Use of unstimulated (random) LH levels may be helpful in diagnosis and has gained popularity in monitoring GnRHa therapy despite lack of validation against stimulated values. The objective of this investigation was to assess the suitability of random LH for monitoring pubertal suppression during GnRHa treatment.Data from a multi-year, multicenter, open-label trial of annual histrelin implants for CPP was used for our analysis. Children meeting clinical and hormonal criteria for CPP, either nave to GnRHa therapy or previously treated with another GnRHa for at least 6months who were being treated at academic pediatric centers were included in the study. Subjects received a single 50-mg subcutaneous histrelin implant annually until final explant at an age determined at the discretion of each investigator. Monitoring visits for physical examination and GnRHa-stimulation testing were performed at regular intervals. The main outcome measure was pubertal suppression during treatment defined by peak LH<4 mIU/mL after GnRHa stimulation.During histrelin treatment, 36 children underwent a total of 308 monitoring GnRHa stimulation tests. Unstimulated and peak LH levels were positively correlated (r=0.798), and both declined from the first to second year of treatment. MeanSD peak LH level during therapy was 0.620.43 mIU/mL (range, 0.06-2.3), well below the normal prepubertal mean. Mean random LH was 0.350.25 mIU/mL (range, 0.04-1.5), 10-fold higher than the normal prepubertal mean. The random LH levels were above the prepubertal upper threshold (<0.3 mIU/mL) in 48.4% of all tests and in 88.9% of subjects at some point during therapy.In contrast with GnRHa-stimulated LH, unstimulated LH values frequently fail to demonstrate suppression to prepubertal values during GnRHa therapy for CPP, despite otherwise apparent pubertal suppression, and are thus unsuitable for therapeutic monitoring.ClinicalTrial.gov NCT00779103.
View details for DOI 10.1186/1687-9856-2013-20
View details for PubMedID 24295437
Pharmacodynamics of Aqueous Leuprolide Acetate Stimulation Testing in Girls: Correlation between Clinical Diagnosis and Time of Peak Luteinizing Hormone Level JOURNAL OF PEDIATRICS 2012; 161 (4): 757-?
We assessed the pharmacodynamics of a 3-hour leuprolide stimulation test in 11 girls with precocious puberty to determine an optimal single sampling time. Luteinizing hormone level following leuprolide stimulation was near maximum by 30 minutes in girls with central precocious puberty, whereas it continued to rise slowly in girls with nonprogressive puberty.
View details for DOI 10.1016/j.jpeds.2012.06.015
View details for Web of Science ID 000309516400039
View details for PubMedID 22809662
Efficacy and Safety of Leuprolide Acetate 3-Month Depot 11.25 Milligrams or 30 Milligrams for the Treatment of Central Precocious Puberty JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2012; 97 (5): 1572-1580
GnRH agonist (GnRHa) monthly injections are frequently used in the treatment of central precocious puberty (CPP). The 3-month leuprolide depot 11.25- and 30-mg formulations are newly approved treatment options.The aim of the study was to investigate the safety and efficacy of leuprolide acetate 3-month depot formulations for the treatment of CPP in children.This was a phase III, randomized, open-label, dose-ranging 6-month study.Twenty-two U.S. medical centers (including Puerto Rico) participated.Children diagnosed with CPP (n = 84), who were either treatment naive or previously treated with GnRHa, were recruited. Chronological age at onset of pubertal signs was less than 8 yr in girls and less than 9 yr in boys, and bone age was advanced over chronological age at least 1 yr.Leuprolide acetate depot (11.25 or 30 mg) was administered im every 3 months.Biochemical [peak-stimulated LH, estradiol (girls), and testosterone (boys)] and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed.Peak-stimulated LH was suppressed in the 11.25- and 30-mg dose groups in 78.4 and 95.2%, respectively, of children from months 2 through 6. There were nine treatment failures (peak-stimulated LH >4 IU/liter) in the 11.25-mg group and two in the 30-mg group. Basal sex steroid suppression, growth rates, pubertal progression, bone age advancement, and adverse events were similar with either dose.Treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, was well tolerated, and may positively impact patient convenience and compliance.
View details for DOI 10.1210/jc.2011-2704
View details for Web of Science ID 000303915900048
View details for PubMedID 22344198
A Randomized Trial of 1-and 3-Month Depot Leuprolide Doses in the Treatment of Central Precocious Puberty JOURNAL OF PEDIATRICS 2011; 159 (6): 982-U148
To compare 1-month and 3-month depot formulations of leuprolide acetate (DL), a gonadotropin-releasing hormone analog, in the treatment of central precocious puberty (CPP).Subjects with CPP nave to therapy were randomized to 7.5 mg of 1-month DL, 11.25 mg of 3-month DL, or 22.5 mg of 3-month DL. Stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and estradiol levels, growth velocity, and bone age progression were examined in a 2-year period.Forty-nine female and 5 male subjects with CPP were randomized. Mean stimulated LH and FSH levels during treatment were higher in the low-dose 11.25-mg 3-month DL group, and more LH levels >4 IU/L were observed, in comparison with the other two dose groups. Mean LH and FSH levels in the 22.5-mg 3-month group were not different from the monthly DL. No differences in estradiol levels, growth velocity, or bone age progression were observed in dosing groups.All DL doses resulted in prompt and effective suppression of puberty, but higher LH and FSH levels were seen with the 11.25-mg 3-month DL dose. Multi-monthly DL is effective in treating CPP, but higher dosing may be required in some circumstances.
View details for DOI 10.1016/j.jpeds.2011.05.036
View details for Web of Science ID 000296849400021
View details for PubMedID 21798557
Efficacy of Leuprolide Acetate 1-Month Depot for Central Precocious Puberty (CPP): Growth Outcomes During a Prospective, Longitudinal Study. International journal of pediatric endocrinology 2011; 2011 (1): 7-?
Gonadotropin-releasing hormone analogs (GnRHa) are the treatment of choice for CPP. We investigated growth in GnRHa-nave subjects, treated with leuprolide acetate 1-month depot for CPP.This prospective, open-label study had a long-term, observational, follow-up period. Forty-nine females and 6 males were enrolled. Leuprolide acetate depot was administered intramuscularly every 28 days. Height and growth rate during and after treatment until adulthood were measured.Among 30 of 49 females having an adult height (AH) measurement, 29 had target heights available (mean = 163.8 cm) and 27 had pretreatment predicted adult heights (PAHs; mean = 157.4 cm). After treatment, the mean AH at mean age 21.8 years [range 13.7-26.7 years] was 162.5 cm, a mean height gain over baseline PAH of 4.0 cm. The mean height standard deviation score was -0.1 at AH.Treatment of CPP with leuprolide acetate 1-month depot had beneficial effects on growth rate and preservation of AH.ClinicalTrials.gov: NCT00660010.
View details for DOI 10.1186/1687-9856-2011-7
View details for PubMedID 21860633
Leuprolide acetate 1-month depot for central precocious puberty: hormonal suppression and recovery. International journal of pediatric endocrinology 2010; 2010: 398639-?
Methods. This prospective US multicenter trial of leuprolide acetate 1-month depot (7.5-15?mg) for central precocious puberty utilized an open-label treatment period, long-term follow-up, and adult callback. Forty-nine females <9 years old with Tanner breast stage ?2 before 8 years and 6 males <10 years old with Tanner genital stage ?2 before 9 years with stimulated LH ?10?IU/L and bone age advance ?1 year were enrolled. Results. Subjects were treated for 3.9??2.0 years. Mean peak GnRH-stimulated LH and FSH were prepubertal after the first dose and remained suppressed throughout treatment. During treatment, mean estradiol decreased to the limit of detection and mean testosterone decreased but remained above prepubertal norms. During posttreatment follow-up (3.5??2.2 years), all patients achieved a pubertal hormonal response within 1 year and menses were reported in all females ?12 years old. No impairment of reproductive function was observed at adulthood (mean age: 24.8 years).
View details for DOI 10.1155/2010/398639
View details for PubMedID 21437000
The US multicenter trial of monthly depot leuprolide for central precocious puberty (CPP): post-treatment outcomes KARGER. 2009: 266-266
The US multicenter trial of monthly depot leuprolide for central precocious puberty (CPP): results during a 4 year treatment period KARGER. 2009: 270-271
Results of a second year of therapy with the 12-month histrelin implant for the treatment of central precocious puberty. International journal of pediatric endocrinology 2009; 2009: 812517-?
Background. Gonadotropin releasing hormone analogs (GnRHas) are standard of care for central precocious puberty (CPP). The histrelin subcutaneous implant is safe and effective in the treatment of CPP for one year. Objective. The study evaluates a second year of therapy in children with CPP who received a new implant after one year of treatment. Methods. A prospective one-year study following an initial 12-month treatment period was conducted. Results. Thirty-one patients (29 girls) aged 7.7 +/- 1.5 years received a second implant. Eighteen were nave to GnRHa therapy at first implantation. Peak LH declined from 0.92 +/- 0.58 mIU/mL at 12 months to 0.51 +/- 0.33 mIU/mL at 24 months (P < .0001) in nave subjects, and from 0.74 +/- 0.50 mIU/mL at 12 months to 0.45 +/- 0.35 mIU/mL at 24 months (P = .0081) in previously treated subjects. Predicted adult height increased by 5.1 cm at 24 months (P = .0001). Minor implant site reactions occurred in 61%, while minor difficulties with explantation occurred in 32.2% of subjects. Conclusion. The histrelin implant demonstrates profound hypothalamic-pituitary-gonadal axis suppression when a new implant is placed for a second year of treatment. Prospective follow-up of this therapeutic modality for the treatment of CPP is needed.
View details for DOI 10.1155/2009/812517
View details for PubMedID 19956699
Correlation of Clinical and Biochemical Findings with Diabetic Ketoacidosis-Related Cerebral Edema in Children Using Magnetic Resonance Diffusion-Weighted Imaging JOURNAL OF PEDIATRICS 2008; 153 (4): 541-546
To determine clinical and biochemical factors influencing cerebral edema formation during diabetic ketoacidosis (DKA) in children.We used magnetic resonance diffusion-weighted imaging to quantify edema formation. We measured the apparent diffusion coefficient (ADC) of brain water during and after DKA treatment in 26 children and correlated ADC changes with clinical and biochemical variables.Mean ADC values were elevated during DKA treatment compared with baseline (8.13 +/- 0.47 vs 7.74 +/- 0.49 x 10(-4) mm(2)/sec, difference in means 0.40, 95% CI: 0.25 to 0.55, P < .001). Children with altered mental status during DKA had greater elevation in ADC. ADC elevation during DKA was positively correlated with initial serum urea nitrogen concentration (correlation coefficient 0.41, P = .03) and initial respiratory rate (correlation coefficient 0.61, P < .001). ADC elevation was not significantly correlated with initial serum glucose, sodium or effective osmolality, nor with changes in glucose, sodium or osmolality during treatment. Multivariable analyses identified the initial urea nitrogen concentration and respiratory rate as independently associated with ADC elevation.The degree of edema formation during DKA in children is correlated with the degree of dehydration and hyperventilation at presentation, but not with factors related to initial osmolality or osmotic changes during treatment. These data support the hypothesis that CE is related to cerebral hypoperfusion during DKA, and that osmotic fluctuations during DKA treatment do not play a primary causal role.
View details for DOI 10.1016/j.jpeds.2008.04.018
View details for Web of Science ID 000260101600023
View details for PubMedID 18589447
Elevated serum amylase and lipase in pediatric diabetic ketoacidosis PEDIATRIC CRITICAL CARE MEDICINE 2008; 9 (4): 418-422
Pancreatic enzyme concentrations are frequently elevated in children with diabetic ketoacidosis (DKA). We sought to determine the clinical and biochemical characteristics associated with patients with these elevations. Our hypothesis was that pancreatic enzyme elevations would be associated with biochemical markers of hypoperfusion.Prospective cohort study.Three university-affiliated children's hospitals.We collected data on consecutive children <18 yrs of age hospitalized with the diagnosis of DKA.Serum electrolyte and lactate concentrations and venous pH and Pco2 were measured every 3 hrs from hours 0 to 12 and then every 6 hrs until hour 24. Serum calcium, phosphate, and magnesium concentrations were measured every 6 hrs from hours 0 to 24. Serum amylase, lipase, and triglyceride concentrations were measured at hour 0 and then 12, 24, and 48 hrs after the initiation of therapy.We performed multivariable analyses to test for associations between clinical variables and pancreatic enzyme elevation in 67 children with DKA. Lipase was elevated in 21 (31%) and amylase in 16 (24%) of the children. Pancreatic enzyme values peaked 12-24 hrs after admission. There was no significant correlation between pancreatic enzyme elevation and abdominal pain. In multivariable analyses, an elevated blood urea nitrogen (BUN) concentration was associated with elevated serum amylase (odds ratio 1.04 per unit increase; 95% confidence interval, 1.01-1.09; p = .02), and elevated BUN concentrations and hypophosphatemia were associated with elevated serum lipase (odds ratio 1.04 per unit increase; 95% confidence interval, 1.00-1.08; p = .04; and odds ratio 0.35 per unit increase; 95% confidence interval, 0.15-0.81; p = .01, respectively).Elevation of pancreatic enzymes is common in children with DKA, but clinical pancreatitis is rare. Pancreatic enzyme levels reach a peak 12-24 hrs after initiation of treatment for DKA. Pancreatic enzyme elevation is associated with increased BUN concentrations at presentation but is not associated with abdominal pain.
View details for DOI 10.1097/PCC.0b013e318172e99b
View details for Web of Science ID 000257627600011
View details for PubMedID 18496406
Efficacy and safety of histrelin subdermal implant in children with central precocious puberty: A multicenter trial JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2007; 92 (5): 1697-1704
GnRH analog (GnRHa) therapy for central precocious puberty (CPP) typically involves im injections. The histrelin implant is a new treatment that provides a continuous slow release of the GnRHa histrelin.The objective of the study was to investigate the safety and efficacy of the subdermal histrelin implant for the treatment of CPP in treatment naive and previously treated children.This was a phase III, open-label, prospective study of 1-yr duration.The study was conducted at nine U.S. medical centers.Girls ages 2-8 yr (naive) or 2-10 yr (previously treated) and boys 2-9 yr (naive) or 2-11 yr (previously treated) with clinical evidence of CPP and a pretreatment pubertal response to leuprolide stimulation were eligible.A 50-mg histrelin implant was inserted sc in the inner upper arm.Peak LH after GnRHa stimulation testing and estradiol (girls) and testosterone (boys) were the main outcome measures.Thirty-six subjects (20 naive) were enrolled. By 1 month, peak LH fell from 28.2 +/- 19.97 (naive) to 0.8 +/- 0.39 mIU/ml (P < 0.0001) and from 2.1 +/- 2.15 (previously treated) to 0.5 +/- 0.32 mIU/ml (P < 0.0056). Estradiol suppressed from 24.5 +/- 22.27 (naive) to 5.9 +/- 2.37 pg/ml (P = 0.0016) and remained suppressed in previously treated subjects, as did testosterone. Suppression was maintained throughout the study. No significant adverse events occurred.The subdermal histrelin implant achieves and maintains excellent suppression of peak LH and sex steroid levels for 1 yr in children with CPP. The treatment is well tolerated. Long-term studies are needed to confirm these results.
View details for DOI 10.1210/jc.2006-2479
View details for Web of Science ID 000246221200023
View details for PubMedID 17327379
Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis AMERICAN JOURNAL OF NEURORADIOLOGY 2007; 28 (5): 895-899
Subclinical cerebral edema occurs in many, if not most, children with diabetic ketoacidosis (DKA) and may be an indicator of subtle brain injury. Brain ratios of N-acetylaspartate (NAA) to creatine (Cr), measured by proton MR spectroscopy, decrease with neuronal injury or dysfunction. We hypothesized that brain NAA/Cr ratios may be decreased in children in DKA, indicating subtle neuronal injury.Twenty-nine children with DKA underwent cerebral proton MR spectroscopy during DKA treatment (2-12 hours after initiating therapy) and after recovery from the episode (72 hours or more after the initiation of therapy). We measured peak heights of NAA, Cr, and choline (Cho) in 3 locations within the brain: the occipital gray matter, the basal ganglia, and periaqueductal gray matter. These regions were identified in previous studies as areas at greater risk for neurologic injury in DKA-related cerebral edema. We calculated the ratios of NAA/Cr and Cho/Cr and compared these ratios during the acute illness and recovery periods.In the basal ganglia, the ratio of NAA/Cr was significantly lower during DKA treatment compared with that after recovery (1.68 +/- 0.24 versus 1.86 +/- 0.28, P<.005). There was a trend toward lower NAA/Cr ratios during DKA treatment in the periaqueductal gray matter (1.66 +/- 0.38 versus 1.91 +/- 0.50, P=.06) and the occipital gray matter (1.97 +/- 0.28 versus 2.13 +/- 0.18, P=.08). In contrast, there were no significant changes in Cho/Cr ratios in any region.NAA/Cr ratios are decreased in children during DKA and improve after recovery. This finding suggests that during DKA neuronal function or viability or both are compromised and improve after treatment and recovery.
View details for Web of Science ID 000246601600028
View details for PubMedID 17494665
Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 2006; 91 (5): 1862-1867
Dosing of monthly depot leuprolide (DL) in central precocious puberty (CPP) varies considerably. U.S. practitioners use 7.5-15 mg, in contrast with the international standard of 3.75 mg. Pubertal suppression using the newer 3-month DL also has been reported from Europe. To date there have been no direct comparisons of these different DL doses.In an open 12-month protocol, we tested the efficacy of three DL doses (7.5 mg- and 3.75 mg-1 month and 11.25 mg-3 month) given sequentially to subjects treated for CPP. Primary outcome measures were stimulated gonadotropin (Gn) levels at 12-wk intervals. The null hypothesis was no difference among doses.Both existing and new patients with CPP received our standard therapy (DL 7.5 mg every 4 wk) for a minimum of 24 wk. In subjects with DL-stimulated LH 2 IU/liter or less, the dose was changed to 3.75 mg every 4 wk and evaluated 12 wk later. Subjects who met LH criteria (<4.5 IU/liter) on 3.75 mg then received a single dose of 11.25 mg-3 month and were reevaluated 12 wk later. Serum LH/FSH and sex steroids were obtained 40 min after DL injection.Thirty subjects were enrolled (20 naive; 24 girls, 6 boys), and 21 were evaluated on all three DL doses. DL-stimulated LH levels (mean +/- sd) were 1.30 +/- 0.74, 1.73 +/- 0.99, and 2.13 +/- 1.41 on 7.5 mg, 3.75 mg, and 11.25 mg-3 month, respectively (7.5 vs. 3.75 mg, P = 0.019; 7.5 mg vs. 11.25 mg-3 month, P = 0.004, Wilcoxon ranked sign test). Mean FSH levels were 2.86 +/- 1.91, 3.91 +/- 1.98, and 3.96 +/- 1.34, respectively (7.5 vs. 3.75 mg, P = 0.017; 7.5 mg vs. 11.25 mg-3 month, P = 0.020). No differences were detected in mean sex steroid levels.Stimulated LH and FSH levels were significantly higher during therapy with both the 3.75 mg and 11.25 mg-3 month depot leuprolide doses, compared with 7.5 mg, contradicting the null hypothesis of no difference. These data suggest that low-dose 1- and 3-month DL preparations are associated with persistently greater gonadal stimulation in most CPP patients, but the LH/FSH results were not corroborated by differences in sex steroid levels. Whether various DL doses lead to long-term therapeutic differences remains to be determined.
View details for DOI 10.1210/jc.2005-1500
View details for Web of Science ID 000237330000037
View details for PubMedID 16449344
Too young to grow. Diagnosis and treatment of precocious puberty. Advance for nurse practitioners 2006; 14 (4): 45-48
Frequency of sub-clinical cerebral edema in children with diabetic ketoacidosis PEDIATRIC DIABETES 2006; 7 (2): 75-80
Symptomatic cerebral edema occurs in approximately 1% of children with diabetic ketoacidosis (DKA). However, asymptomatic or subclinical cerebral edema is thought to occur more frequently. Some small studies have found narrowing of the cerebral ventricles indicating cerebral edema in most or all children with DKA, but other studies have not detected narrowing in ventricle size. In this study, we measured the intercaudate width of the frontal horns of the lateral ventricles using magnetic resonance imaging (MRI) in children with DKA during treatment and after recovery from the DKA episode. We determined the frequency of ventricular narrowing and compared clinical and biochemical data for children with and without ventricular narrowing. Forty-one children completed the study protocol. The lateral ventricles were significantly smaller during DKA treatment (mean width, 9.3 +/- 0.3 vs. 10.2 +/- 0.3 mm after recovery from DKA, p < 0.001). Children with ventricular narrowing during DKA treatment (22 children, 54%) were more likely to have mental status abnormalities than those without narrowing [12/22 vs. 4/19 with Glasgow Coma Scale (GCS) scores below 15 during therapy, p = 0.03]. Multiple logistic regression analysis revealed that a lower initial PCO2 level was significantly associated with ventricular narrowing [odds ratio (OR) = 0.88, 95% confidence interval (95% CI) = 0.78-0.99, p = 0.047). No other variables analyzed were associated with ventricular narrowing in the multivariate analysis. We conclude that narrowing of the lateral ventricles is evident in just over half of children being treated for DKA. Although children with ventricular narrowing did not exhibit neurological abnormalities sufficient for a diagnosis of 'symptomatic cerebral edema', mild mental status abnormalities occurred frequently, suggesting that clinical evidence of cerebral edema in children with DKA may be more common than previously reported.
View details for Web of Science ID 000236962500002
View details for PubMedID 16629712
Detection of cerebral beta-hydroxy butyrate, acetoacetate, and lactate on proton MR spectroscopy in children with diabetic ketoacidosis AMERICAN JOURNAL OF NEURORADIOLOGY 2005; 26 (5): 1286-1291
Ketone bodies provide important alternate fuel for brain metabolism, and their transport into the brain increases with prolonged fasting. During diabetic ketoacidosis (DKA), serum ketone concentrations markedly increase; however, little is known about whether ketone bodies accumulate in cerebral tissues during DKA. We used proton MR spectroscopy (MRS) to detect cerebral beta-hydroxy butyrate (betaOHB) and acetone/acetocaetate (AcAc) in children with DKA.Twenty-five children underwent brain MRS: nine within 4 hours of the start of treatment for DKA; 11, at 4-8 hours; and five, at 8-12 hours. MRS was repeated after their recovery from the DKA episode at > or =72 hours after the start of treatment. MRS was evaluated for peaks corresponding to betaOHB (doublet centered on 1.20 ppm) and lactate (doublet centered on 1.33 ppm). Difference spectroscopy was used to identify the AcAc peak at 2.22-2.26 ppm.betaOHB was detected in 13 children (52%), more frequently within 4 hours (eight children, 89%) than after 4 hours (five children, 31%). AcAc was detected in 15 children (60%), more frequently at >4 hours after the start of treatment (12 patients, 75%) than in the first 4 hours (three patients, 33%). Lactate was detected in five children (18%), all within the first 8 hours of treatment.In children, betaOHB and AcAc accumulate in the brain during DKA, and they can be detected on MRS. Care should be taken in interpreting MRS results in patients with DKA to avoid erroneously attributing betaOHB peaks to lactate.
View details for Web of Science ID 000229306100053
View details for PubMedID 15891198
Comparison of depot leuprolide doses in central precocious puberty BIOSCIENTIFICA LTD. 2005
Mechanism of cerebral edema in children with diabetic ketoacidosis JOURNAL OF PEDIATRICS 2004; 145 (2): 164-171
Cerebral edema during diabetic ketoacidosis (DKA) has been attributed to osmotic cellular swelling during treatment. We evaluated cerebral water distribution and cerebral perfusion during DKA treatment in children.We imaged 14 children during DKA treatment and after recovery, using both diffusion and perfusion weighted magnetic resonance imaging (MRI). We assessed the apparent diffusion coefficients (ADCs) and measures reflecting cerebral perfusion.The ADC was significantly elevated during DKA treatment (indicating increased water diffusion) in all regions except the occipital gray matter. Mean reductions in the ADC from initial to postrecovery MRI were: basal ganglia 4.7 +/- 2.5 x 10(-5) mm(2)/s (P=.002), thalamus 3.7 +/- 2.8 x 10(-5) mm(2)/s, (P=.002), periaqueductal gray matter 4.3 +/- 5.1 x 10(-5) mm(2)/s (P=.03), and frontal white matter 2.0 +/- 3.1 x 10(-5) mm(2)/s (P=.03). In contrast, the ADC in the occipital gray matter increased significantly from the initial to postrecovery MRI (mean increase 3.9 +/- 3.9 x 10(-5) mm(2)/s, P=.004). Perfusion MRI during DKA treatment revealed significantly shorter mean transit times (MTTs) and higher peak tracer concentrations, possibly indicating increased cerebral blood flow (CBF).Elevated ADC values during DKA treatment suggests a vasogenic process as the predominant mechanism of edema formation rather than osmotic cellular swelling.
View details for DOI 10.1016/j.jpeds.2004.03.045
View details for Web of Science ID 000223406200008
View details for PubMedID 15289761
Comparison of depot leuprolide doses in central precocious puberty NATURE PUBLISHING GROUP. 2004: 155A-155A
Functional neuroanatomy of spatial orientation processing in Turner syndrome CEREBRAL CORTEX 2004; 14 (2): 174-180
Turner syndrome (TS), a neurogenetic disorder characterized by the absence of one X chromosome in a phenotypic female, is frequently associated with visuospatial impairments. We investigated the neural mechanisms underlying deficits in spatial orientation processing in TS. Thirteen subjects with TS and 13 age-matched typically developing controls underwent neuropsychological assessments and were scanned using functional MRI while they performed easy and difficult versions of a judgment of line orientation (JLO) task. Controls and subjects with TS activated parietal-occipital regions involved in spatial orientation during the JLO task. However, activation was significantly less in the TS group. Control subjects responded to increased task difficulty by recruiting executive frontal areas whereas subjects with TS did not activate alternate brain regions to meet increased task demands. Subjects with TS demonstrate activation deficits in parietal-occipital and frontal areas during the JLO task. Activation, and possibly deactivation, deficits in these areas may be responsible for the visuospatial deficits observed in females with TS.
View details for DOI 10.1093/cercor/bhg116
View details for Web of Science ID 000187975800006
View details for PubMedID 14704214
Pitfalls in the hunt for osteoporosis AMERICAN JOURNAL OF MEDICINE 2003; 115 (4): 322-323
Estrogen excess associated with novel gain-of-function mutations affecting the aromatase gene NEW ENGLAND JOURNAL OF MEDICINE 2003; 348 (19): 1855-1865
Gynecomastia of prepubertal onset may result from increased estrogen owing to excessive aromatase activity in extraglandular tissues. A gene in chromosome 15q21.2 encodes aromatase, the key enzyme for estrogen biosynthesis. Several physiologic tissue-specific promoters regulate the expression of aromatase, giving rise to messenger RNA (mRNA) species with an identical coding region but tissue-specific 5'-untranslated regions in placenta, gonads, brain, fat, and skin.We studied skin, fat, and blood samples from a 36-year-old man, his 7-year-old son, and an unrelated 17-year-old boy with severe gynecomastia of prepubertal onset and hypogonadotropic hypogonadism caused by elevated estrogen levels.Aromatase activity and mRNA levels in fat and skin and whole-body aromatization of androstenedione were severely elevated. Treatment with an aromatase inhibitor decreased serum estrogen levels and normalized gonadotropin and testosterone levels. The 5'-untranslated regions of aromatase mRNA contained the same sequence (FLJ) in the father and son and another sequence (TMOD3) in the unrelated boy; neither sequence was found in control subjects. These 5'-untranslated regions normally make up the first exons of two ubiquitously expressed genes clustered in chromosome 15q21.2-3 in the following order (from telomere to centromere): FLJ, TMOD3, and aromatase. The aromatase gene is normally transcribed in the direction opposite to that of TMOD3 and FLJ. Two distinct heterozygous inversions reversed the direction of the TMOD3 or FLJ promoter in the patients.Heterozygous inversions in chromosome 15q21.2-3, which caused the coding region of the aromatase gene to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, resulted in severe estrogen excess owing to the overexpression of aromatase in many tissues.
View details for Web of Science ID 000182684100004
View details for PubMedID 12736278
Brain development in Turner syndrome: a magnetic resonance imaging study PSYCHIATRY RESEARCH-NEUROIMAGING 2002; 116 (3): 187-196
Turner syndrome (TS) results from the absence of an X chromosome in females. This genetic condition is associated with specific cognitive deficits and variations in brain volumes. The goal of this study was to use high-resolution magnetic resonance imaging (MRI) to determine morphological variations in TS and to investigate the effects of parental origin of the X chromosome on brain development in TS. MRI brain scans were acquired from 26 girls with TS and 26 age- and gender-matched controls. Seventeen of the TS subjects had a maternally inherited X chromosome (Xm), and nine of the subjects had a paternally inherited X chromosome (Xp). Rater-blind morphometric analyses were conducted to compare tissue volume differences between girls with TS and controls. Three-way analyses were used to compare subgroups and controls. Subjects with TS demonstrated bilateral decreases in parietal gray and occipital white matter accompanied by increased cerebellar gray matter. Subjects with Xm showed decreased occipital white matter and increased cerebellar gray matter compared to controls. No differences were found in comparisons between subjects with Xp and controls or between subjects with Xm and Xp. Results suggest that X monosomy affects posterior cerebral and cerebellar anatomy in TS. While differences between comparisons of Xm and Xp to controls might suggest an imprinting effect, no significant differences were found when the two subgroups were directly compared to each other. Further investigation into the possible role of genomic imprinting is therefore warranted.
View details for Web of Science ID 000180535800005
View details for PubMedID 12477602
Molecular characterization of a ring X chromosome in a male with short stature HUMAN GENETICS 2002; 110 (4): 322-326
We report the molecular characterization of a ring X chromosome that was transmitted from a mother to a male who has short stature and minor dysmorphic features. This represents only the second reported ring X chromosome in a male. The ring is derived from breakage within the Xp pseudoautosomal region (PAR) and just proximal to the Xq PAR. The total amount of deleted material is 700-900 kb DNA and includes six known transcribed genes. Interestingly, SHOX, a gene implicated in short stature, is not deleted from the ring chromosome. Possible pathogenetic explanations for the patient's clinical features include insufficient dosage of deleted genes, a position effect on SHOX expression, and cell death during development because of ring chromosome nondisjunction. The findings are also relevant to observations made of "complete" ring chromosomes.
View details for DOI 10.1007/s00439-002-0685-7
View details for Web of Science ID 000175479900004
View details for PubMedID 11941480
Serum luteinizing hormone rises within minutes after depot leuprolide injection: Implications for monitoring therapy AMER ACAD PEDIATRICS. 2002
To find the time of the serum gonadotropin peak after depot leuprolide injection in children and to show that depot leuprolide therapy can be monitored by measuring serum luteinizing hormone (LH) immediately after injections.We measured concentrations of leuprolide, LH, and follicle-stimulating hormone (FSH) at multiple time points before and after the first dose of depot leuprolide in 14 pubertal children beginning therapy. Gonadotropins and sex steroids were measured again after the fourth dose.Serum leuprolide, LH, and FSH levels rose rapidly after initial injection, reaching sustained elevations at 30 to 120 minutes. The median LH level increased from 2.1 mIU/mL at baseline to a peak of 27.5 mIU/mL at 45 minutes, and FSH increased from 5.2 to 16.5 mIU/mL. After 3 months on therapy, median serum LH after depot leuprolide injection was only 0.83 mIU/mL, similar to levels observed after intravenous or subcutaneous gonadotropin-releasing hormone stimulation in comparable subjects on depot leuprolide.Our pharmacokinetic data demonstrate that free leuprolide present in a depot leuprolide injection is equivalent to gonadotropin-releasing hormone in stimulating a rapid rise in serum gonadotropin concentrations. We propose that a single serum sample for LH obtained 30 to 60 minutes after depot leuprolide injection in children provides a convenient and accurate assessment of treatment efficacy.
View details for Web of Science ID 000173601200012
View details for PubMedID 11826240
Functional neuroanatomy of visuo-spatial working memory in Turner syndrome HUMAN BRAIN MAPPING 2001; 14 (2): 96-107
Turner syndrome (TS), a genetic disorder characterized by the absence of an X chromosome in females, has been associated with cognitive and visuo-spatial processing impairments. We utilized functional MRI (fMRI) to investigate the neural substrates that underlie observed deficits in executive functioning and visuo-spatial processing. Eleven females with TS and 14 typically developing females (ages 7-20) underwent fMRI scanning while performing 1-back and 2-back versions of a standard visuo-spatial working memory (WM) task. On both tasks, TS subjects performed worse than control subjects. Compared with controls, TS subjects showed increased activation in the left and right supramarginal gyrus (SMG) during the 1-back task and decreased activation in these regions during the 2-back task. In addition, decreased activation in the left and right dorsolateral prefrontal cortex (DLPFC) and caudate nucleus was observed during the 2-back task in TS subjects. Activation differences localized to the SMG, in the inferior parietal lobe, may reflect deficits in visuo-spatial encoding and WM storage mechanisms in TS. In addition, deficits in the DLPFC and caudate may be related to deficits in executive function during WM performance. Together these findings point to deficits in frontal-striatal and frontal-parietal circuits subserving multiple WM functions in TS.
View details for Web of Science ID 000171325100003
View details for PubMedID 11500993
Ambiguous genitalia. Pediatrics in review 1996; 17 (6): 213-220
The newborn whose genitalia are ambiguous presents a challenge to the pediatrician and the family. A clear understanding of the basis of sex differentiation and timely consultation with a pediatric endocrinologist is critical in the evaluation and determination of sex of rearing in a newborn who has ambiguous genitalia. Sex karyotype and a 17-OHP level may suffice in the initial evaluation of female pseudohermaphroditism because most patients will have virilizing CAH. If male pseudohermaphroditism is suspected on the basis of palpable gonads, we routinely obtain a karyotype, basal adrenal steroid levels, and levels of hCG-stimulated serum testosterone and DHT, then consider a testosterone treatment trial. Physicians who care for children who have ambiguous genitalia must appreciate the family's cultural, religious, and psychological needs and avoid determining sex of rearing before accurate diagnosis is reached.
View details for PubMedID 8857201
Type I diabetes mellitus, ketoacidosis and thromboembolism in an adolescent with Prader-Willi syndrome ACTA PAEDIATRICA 1996; 85 (4): 516-516
A single-sample, subcutaneous gonadotropin-releasing hormone test for central precocious puberty PEDIATRICS 1996; 97 (4): 517-519
We compared a rapid, subcutaneous (SQ), single-sample gonadotropin-releasing hormone (GnRH) stimulation test with the standard multiple-sample, intravenous (IV) GnRH stimulation test used in the evaluation of central precocious puberty (CPP).We evaluated 22 patients presenting with evidence of precocious puberty. GnRH (100 microg) was administered subcutaneously in the clinic setting with single serum luteinizing hormone (LH) measured 40 minutes after injection. A standard IV GnRH stimulation test was performed within 2 weeks, with serum LH obtained at 0, 20, 40, and 60 minutes. LH was assayed by immunochemiluminometric assay.The mean peak LH levels after IV and SQ testing were identical. A significant correlation (r = .88) was found between the LH determined by SQ stimulations and the peak LH determined by IV GnRH testing. CPP was diagnosed (LH, >/- 8 IU/L) by both SQ and IV testing in 7 of 22 patients and was excluded by both tests in 14 of 22 patients. A diagnostic discrepancy between peak IV and SQ results was seen in 1 patient.We conclude that mean GnRH-stimulated LH levels from rapid SQ and standard IV testing are indistinguishable and that individual LH levels by each method are strongly correlated. A rapid SQ GnRH test is a valid tool for laboratory confirmation of CPP.
View details for Web of Science ID A1996UC74700013
View details for PubMedID 8632938
BONE-MINERAL DENSITY DURING TREATMENT OF CENTRAL PRECOCIOUS PUBERTY JOURNAL OF PEDIATRICS 1995; 127 (5): 819-822
Treatment of adults with gonadotropin releasing hormone analogs has resulted in rapid loss in bone mineral density (BMD). We measured lumbar and femoral neck BMD by dual-energy x-ray absorptiometry during 2 years of depot leuprolide therapy in 13 girls (mean age, 7.5 years; mean bone age, 10.9 years). At baseline, BMD was elevated for age and concordant with the advanced skeletal age. During therapy with gonadotropin releasing hormone analog, BMD values increased and BMD standard deviation scores for age and skeletal age did not change.
View details for Web of Science ID A1995TD93100031
View details for PubMedID 7472845
NORMAL RANGES FOR IMMUNOCHEMILUMINOMETRIC GONADOTROPIN ASSAYS JOURNAL OF PEDIATRICS 1995; 127 (1): 40-46
We sought to establish normative data for spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays (ICMA) in children and adolescents.Random serum samples were obtained from 375 normal subjects (0.1 to 17.7 years, 230 female subjects). Intravenous GnRH stimulation tests were performed in 41 normal subjects (4.8 to 18 years, 20 female subjects). Normal ranges were calculated by age and Tanner stage. Immunochemiluminometric assays of LH and FSH concentrations were compared with levels obtained by a sensitive immunofluorometric assay and a less sensitive radioimmunoassay.Random gonadotropin concentrations in normal children followed the pattern of transient elevation in infancy, low but measurable prepubertal levels, and markedly increased values at puberty. Spontaneous LH levels were higher in male infants but were not statistically different in boys and girls after infancy. Mean prepubertal LH was 0.04 +/- 0.04 IU/L (n = 66), rising 100-fold during puberty. Spontaneous FSH levels were much higher than LH values, were higher in female infants, and rose threefold at puberty. Peak GnRH-stimulated LH was identical in prepubertal boys and girls (1.8 +/- 1.3 IU/L, n = 17) and increased 20-fold at puberty. Mean peak GnRH-stimulated FSH was highest in prepubertal female subjects. Luteinizing hormone values measured by ICMA and immunofluorometric assay were highly correlated, but radioimmunoassay levels diverged markedly from ICMA levels at lower concentrations. Because absolute levels were higher, FSH values correlated adequately in the three assays throughout the normal physiologic range.Measurement of LH by ICMA is much more sensitive than older assay methods. Spontaneous LH can be accurately measured by ICMA to the very low levels present in normal prepubertal children, providing a potentially important biochemical discriminator of pubertal status. An ICMA GnRH-stimulated LH level greater than 5 IU/L is suggestive of maturing gonadotropin secretion. The ICMA LH assays provide significant enhancement in sensitivity; these assays should be used when levels may be low, and by their accuracy may reduce the time and expense of testing procedures.
View details for Web of Science ID A1995RH63700006
View details for PubMedID 7608809
SPONTANEOUS SERUM GONADOTROPIN CONCENTRATIONS IN THE EVALUATION OF PRECOCIOUS PUBERTY JOURNAL OF PEDIATRICS 1995; 127 (1): 47-52
We assessed the utility of spontaneous and gonadotropin-releasing hormone (GnRH)-stimulated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels measured by new immunochemiluminometric assays in the evaluation and monitoring of precocious puberty.We evaluated serum gonadotropin values from intravenous GnRH stimulation tests in 49 girls with clinical signs suggesting central precocious puberty (CPP). Because GnRH-stimulated LH has been considered the standard for diagnosing CPP, we used it as the basis for comparison with GnRH-stimulated FSH levels and spontaneous LH and FSH measured by immunochemiluminometric assay.Twenty-six patients had a peak serum LH value above the +2 SD threshold for normal prepubertal female subjects (LH > 5 IU/L). The GnRH-stimulated FSH values had a narrow range and did not discriminate patients with CPP. In contrast, elevations in spontaneous LH and FSH were found to be specific for CPP. Spontaneous LH levels correlated strongly with peak stimulated LH levels in subjects with precocious puberty (r = 0.79) or in control subjects (r = 0.93, both p (0.0001). Spontaneous LH levels in excess of 0.1 IU/L detected true puberty with 94% sensitivity and 88% specificity. Random LH levels in excess of 0.3 IU/L had 100% specificity for CPP.The GnRH-stimulated FSH levels do not adequately differentiate children with and without CPP and have limited utility in the evaluation of precocious puberty. Spontaneous FSH levels are elevated in CPP with fair sensitivity and marked specificity. Elevated random LH, measured by third-generation assay such as immunochemiluminometric assay, is strongly correlated with and highly predictive of elevated peak GnRH-stimulated LH, and is a useful screening tool for CPP.
View details for Web of Science ID A1995RH63700007
View details for PubMedID 7608810
A QUANTITATIVE ASSAY FOR IGF-I AND IGF BINDING-PROTEIN MESSENGER-RNAS - EXPRESSION IN MALIGNANT-MELANOMA CELLS MOLECULAR AND CELLULAR ENDOCRINOLOGY 1995; 110 (1-2): 213-223
The quantification of messenger RNA is central in studies of gene expression. We describe a quantitative assay for specific mRNAs (QASM) that measures mRNAs for insulin-like growth factor-I, IGF binding proteins (IGFBPs) -2, -3, -4, and -5, and beta-actin. The assay utilizes reverse transcription and polymerase chain reaction, followed by an ELISA based DNA assay technique. The use of internal (competitive) quantification standards gave poorly linear results, while external standards gave linear and reproducible results. QASM results correlated with IGFBP protein concentrations in conditioned medium and with mRNA levels determined by Northern blotting. QASM was used to study IGFBP expression in human malignant melanoma cells. Messenger RNA for IGFBP-2, -3, and -5 were present, while IGF-I and IGFBP-4 mRNAs were not detected. IGFBP-2 and -3 expression was increased in a dose dependent manner by treatment with IGF-I. Protein concentrations in conditioned media paralleled mRNA levels. QASM is a sensitive, specific, and reproducible approach to determining mRNA levels.
View details for Web of Science ID A1995QZ08800025
View details for PubMedID 7545621
CRITERIA FOR DIAGNOSIS OF CENTRAL PRECOCIOUS PUBERTY NATURE PUBLISHING GROUP. 1995: A88-A88
NOVEL SPINAL DYSPLASIA IN 2 GENERATIONS AMERICAN JOURNAL OF MEDICAL GENETICS 1995; 56 (1): 90-93
We report on a father and son with a previously undescribed skeletal abnormality and severe short stature. Antenatal sonographic evaluation of the propositus (son), obtained due to maternal pre-eclampsia, suggested an abnormal spine. At birth, no congenital anomalies were noted and transition to extra-uterine life was smooth. Radiographs performed five days after birth showed spina bifida, hemivertebrae in the mid-thoracic region, and widened lumbar interpedicular distances. MRI of the lower thoracic and lumbar vertebrae documented crescent-shaped appearance of the affected vertebrae and abnormally narrow A-P diameter of the vertebral bodies. Intervertebral discs were small, and the posterior elements, as well as the spinous processes of the affected vertebrae, were markedly hypoplastic. However, there was no narrowness of the spinal canal, and the limbs were unaffected. CT scan with three-dimensional reformatting of the thoracic and lumbar vertebrae documented unusual sagittal clefting of all of the vertebral bodies, which has previously been undescribed. The father had severe kyphoscoliosis and a height of 131.6 cm (-7.5 S.D.). Radiographically, he was found to have multiple segmentation anomalies and diminished A-P diameter of his affected vertebral bodies. The multiple vertebral anomalies are the probable cause for the father's severe kyphoscoliosis. The pattern of inheritance suggests that an autosomal dominant gene is responsible for this condition and that the father represents a de novo mutation. These radiographic abnormalities have not been described previously and represent a new form of vertebral spinal dysplasia.
View details for Web of Science ID A1995QJ89300019
View details for PubMedID 7747794
Role of growth hormone therapy in Turner syndrome SPRINGER-VERLAG. 1995: 258-268
LOCAL REACTIONS TO LUTEINIZING-HORMONE-RELEASING HORMONE ANALOG THERAPY - REPLY JOURNAL OF PEDIATRICS 1995; 126 (1): 159-160
Estrogen for feminization: A review TURNER SYNDROME IN A LIFE-SPAN PERSPECTIVE: RESEARCH AND CLINICAL ASPECTS 1995; 1089: 219-226
A multicenter trial of depot leuprolide for central precocious puberty NEUROBIOLOGY OF PUBERTY 1995: 313-318
RECOMMENDATIONS FOR DIAGNOSIS, TREATMENT, AND MANAGEMENT OF INDIVIDUALS WITH TURNER SYNDROME ENDOCRINOLOGIST 1994; 4 (5): 351-358
ALTERED BODY-COMPOSITION AND INCREASED FREQUENCY OF DIVERSE MALIGNANCIES IN INSULIN-LIKE GROWTH FACTOR-II TRANSGENIC MICE JOURNAL OF BIOLOGICAL CHEMISTRY 1994; 269 (19): 13779-13784
The physiological role of insulin-like growth factor (IGF) II (IGF-II) in adult humans is poorly understood. Rather high levels of IGF-II persist in adult human serum, whereas, in rodents, IGF-II levels are very low. To investigate the physiological and carcinogenic effects of persistently elevated IGF-II in adults, we have produced two lines of transgenic mice in which high levels of IGF-II (20- or 30-fold increase above normal) are persistently maintained in the blood. The transgene is driven by the major urinary protein promoter, and it is highly expressed in the liver and perputial glands in both lines. The adult transgenic mice are smaller than controls, and their body composition is altered. Their lean body mass is reduced by 5-8%, whereas fat mass is reduced between 44 and 77%. The mice expressing the highest level of IGF-II (30x) develop hypoglycemia and hypoinsulinemia and IGF-I levels are normal. Mice in the lower expression line (20-fold elevated IGF-II) develop hypoglycemia progressively over their lifetime. Mice from both lines also develop a diverse spectrum of tumors at a higher frequency than controls after 18 months of age, and the most frequent types of tumors are hepatocellular carcinomas and lymphomas. Squamous cell carcinoma, sarcoma, and thyroid carcinomas also occurred in our test group. The long latent period before tumors arise and the wide spectrum of tumor types suggest that IGF-II may function primarily as a tumor progression factor in mice via autocrine and endocrine mechanisms of action.
View details for Web of Science ID A1994NL60600013
View details for PubMedID 7514593
OCCULT CELIAC-DISEASE - NOT A CAUSE OF SHORT STATURE NATURE PUBLISHING GROUP. 1994: A109-A109
COMPARISON OF A RAPID, SINGLE-SAMPLE SUBCUTANEOUS GNRH STIMULATION TEST WITH STANDARD-IV GNRH TESTING IN THE EVALUATION OF PRECOCIOUS PUBERTY NATURE PUBLISHING GROUP. 1994: A98-A98
A PROSPECTIVE RANDOMIZED TRIAL OF GROWTH-RESPONSE TO 2 DOSAGES OF RHGH NATURE PUBLISHING GROUP. 1994: A93-A93
USE AND ABUSE OF HUMAN GROWTH-HORMONE ANNUAL REVIEW OF MEDICINE 1994; 45: 407-420
Recombinant human growth hormone (hGH) has been available for nearly a decade. Side effects are rare. Its efficacy in promoting growth acceleration has been widely confirmed in children with GH deficiency (GHD), Turner syndrome, idiopathic short stature, chronic renal failure, and a variety of other conditions. The dramatic increase in height velocity in the first year of therapy partially attenuates in subsequent years in all patient groups, and convincing final height data are only available in GHD and Turner syndrome. Pediatric endocrinologists continue to be troubled by definitions of GHD. Although profound GHD is relatively obvious, other patients with severe growth failure but borderline or normal endocrine testing also respond to hGH therapy. Thus many endocrinologists use auxologic criteria [e.g. low growth velocity, height < -3 standard deviation (SD), poor predicted adult height] as the de facto basis for therapy, leading to a blurred distinction between treatment of disease and enhancement of normal characteristics and, finally, raising questions about the ultimate benefit of hGH therapy. Brief clinical trials of hGH therapy in adults both with and without GHD have reported increased muscle mass, decreased fat, and improvement in quality of life. Internists may soon be faced with treatment decisions analogous to those confronting pediatricians, i.e. whether to use hGH to repair aspects of the normal aging process.
View details for Web of Science ID A1994NF16800032
View details for PubMedID 8198391
LOCAL REACTIONS TO DEPOT LEUPROLIDE THERAPY FOR CENTRAL PRECOCIOUS PUBERTY - REPLY JOURNAL OF PEDIATRICS 1993; 123 (2): 335-335
NEW CONCEPTS IN INSULIN-LIKE GROWTH-FACTOR RECEPTOR PHYSIOLOGY GROWTH REGULATION 1993; 3 (2): 113-123
TURNER SYNDROME ADOLESCENTS RECEIVING GROWTH-HORMONE ARE NOT OSTEOPENIC JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 1993; 76 (4): 861-866
Deficits in bone mineral have been widely reported in Turner syndrome. The bone mineral status of 19 adolescents with Turner syndrome (16 receiving GH therapy) was evaluated by dual photon absorptiometry of the lumbar spine and whole body and compared with a normal female control group (n = 45) with the same mean age (14.3 yr). The conventional measurements of bone mass, bone mineral content (BMC = g), and bone mineral density (BMD = g/cm2), as well as bone mineral apparent density (BMAD = g/cm3), an expression of bone mineral adjusted for bone volume, were determined for both sites. Although mean BMC was decreased in Turner females, mean BMD and BMAD in the two groups were not significantly different. Analyzed in relation to chronologic age, bone age, height, and pubertal status, mean BMD and BMAD values in Turner subjects were equal to or greater than that of controls. BMD and BMAD were elevated in the Turner group vs. controls matched for height. In subjects with bone age less than or equal to 12.5 yr, mean spinal BMAD was unexpectedly greater in Turner patients compared with controls (0.148 +/- 0.011 vs. 0.134 +/- 0.013, P = 0.009). When data were analyzed by pubertal status, mean spinal BMD and BMAD in subjects with Tanner breast stages 1-2 were higher in the Turner group than in the controls (BMAD 0.146 +/- 0.011 vs. 0.132 +/- 0.015, P = 0.015). No differences were seen in mid- to late pubertal females. Bone mineral properties were additionally reassessed after a mean interval of 1.3 yr in 10 of the subjects with Turner syndrome. Percentage increases in mean follow-up spinal BMD and BMAD were greater in 5 subjects begun on estrogen replacement than in 5 untreated patients. We conclude that: 1) bone mineral values in adolescents with Turner syndrome on GH therapy are not abnormal, 2) lumbar bone mineral is greater in younger Turner adolescents matched with controls for bone age or pubertal status, a difference which could relate to GH therapy, and 3) estrogen therapy may augment bone mineral accretion in Turner syndrome, but early estrogen replacement cannot be justified on the basis of bone mineral status.
View details for Web of Science ID A1993KW77300012
View details for PubMedID 8473397
EFFECTS OF ESTROGEN ON GROWTH-HORMONE FOLLOWING CLONIDINE STIMULATION AMERICAN JOURNAL OF DISEASES OF CHILDREN 1993; 147 (1): 63-65
To test the usefulness of estrogen priming to enhance the growth hormone (GH) response following stimulation with clonidine hydrochloride in short children.Randomized and patient series.Pediatric endocrine clinic in a referral center.Seventy-three children (63% male) between 1.8 and 15.4 years of age (mean age, 8.8 years) with growth problems who underwent clonidine GH stimulation tests were randomly assigned to receive either estrogen pretreatment or no pretreatment. An additional 49 subjects, seen before or after the randomized study and who did not receive conjugated estrogen, are also described.Consecutive sample.Estrogen pretreatment consisted of 2.5 mg of conjugated estrogen (Premarin) to be taken the evening before and the morning of the clonidine GH stimulation test. Growth hormone concentrations were determined before and 60 and 90 minutes after the subjects received oral clonidine hydrochloride (5 micrograms/kg) by a laboratory blinded to the subject's estrogen status. Growth hormone concentrations greater than 10 micrograms/L were considered normal.Eight of the 73 subjects failed both clonidine and arginine-insulin GH stimulation tests. We analyzed the GH data from the 65 GH-sufficient subjects to determine the effect of estrogen pretreatment on the specificity of the clonidine GH stimulation test. There were no statistically significant differences in the mean GH concentrations between the two groups at any time point during the test.Our data demonstrate that estrogen priming does not improve the diagnostic yield of clonidine GH stimulation tests.
View details for Web of Science ID A1993KG48300017
View details for PubMedID 8380310
MANAGEMENT OF SEXUAL-DIFFERENTIATION DISORDERS RAVEN PRESS. 1993: 27-45
MITOGENIC EFFECTS OF HUMAN RECOMBINANT INSULIN ON B-CELL PRECURSOR ACUTE LYMPHOBLASTIC-LEUKEMIA CELLS LEUKEMIA 1992; 6 (11): 1134-1142
Insulin and the insulin-like growth factors (IGF-I, IGF-II) constitute a family of peptides capable of stimulating diverse cellular responses, including cell proliferation. In order to determine the effects of these peptides on malignant cells, we analyzed the expression and function of insulin, IGF-I, and IGF-II receptors on B-cell precursor acute lymphoblastic leukemia (BCP ALL) cell lines, utilizing competitive binding, affinity crosslinking, and cell proliferation assays. The BCP ALL cells bound to each peptide with mean specific binding for 125I-insulin, 125I-IGF-I, and 125I-IGF-II of 19.6%, 7.1%, and 4.3% of radioligand added, respectively. Competitive binding to intact cells demonstrated that 125I-IGF-I was displaced by IGF-I = IGF-II > insulin, 125I-IGF-II was displaced by IGF-II > insulin = IGF-I, and 125I-insulin was displaced by insulin > IGF-II > IGF-I. These data were remarkable for the potency of IGF-II displacement of 125I-IGF-I and 125I-insulin. Affinity crosslinking of radioligands to SUP-B2 cell membranes demonstrated the high affinity insulin and IGF-I (type 1 IGF) receptors. IGF binding proteins were also present in BCP ALL cell membrane preparations. In the cell proliferation studies, insulin stimulated a 50-130% increase in leukemic cell growth with a half-maximal concentration of 0.1-3.0 ng/ml in three BCP ALL cell lines. The proliferative response to insulin was blocked by the addition of an insulin receptor antibody. However, no response was observed with IGF-I, and IGF-II was only weakly mitogenic with a proliferative response noted at 100 ng/ml. Thus, while BCP ALL cells possess receptors for insulin and IGF-I, only the insulin receptor mediated a proliferative response.
View details for Web of Science ID A1992JZ29300007
View details for PubMedID 1434795
2-YEAR RESULTS OF TREATMENT WITH DEPOT LEUPROLIDE ACETATE FOR CENTRAL PRECOCIOUS PUBERTY JOURNAL OF PEDIATRICS 1992; 121 (4): 634-640
We report results from 2 years of therapy with the long-acting form of the gonadotropin-releasing hormone (GnRH) analog leuprolide acetate, which was previously reported in short-term trials to be efficacious in the treatment of central precocious puberty. Thirteen girls and two boys, aged 1.9 to 9.7 years, who satisfied clinical criteria including GnRH-stimulated luteinizing hormone (LH) greater than 10 IU/L (mean radioimmunoassay LH, 29.1 +/- 5.54 IU/L), received depot leuprolide, 6 to 15 mg intramuscularly every 4 weeks. Estradiol (or testosterone), insulin-like growth factor I, and GnRH-stimulated gonadotropins were obtained at baseline, at 2 months, and at 6-month intervals with bone age determinations. Pubertal progression ceased in all patients, and menses did not occur. Mean increase in height during therapy was 5.77 +/- 2.0 cm/yr. Predicted adult height increased over baseline by 5.52 +/- 1.16 cm at 18 months. Mean estradiol values in the girls declined from 3.3 +/- 0.6 to 0.60 +/- 0.03 ng/dl, with no overlap of baseline and treatment values. The mean basal LH value was unchanged by therapy; mean basal and peak LH values for all follow-up GnRH stimulation tests were 4.05 +/- 0.57 and 4.95 +/- 0.70 IU/L, respectively. Basal and peak follicle-stimulating hormone (FSH) values were suppressed from 4.10 +/- 0.62 and 10.06 +/- 1.34 IU/L, respectively, to generally undetectable levels (< 1). Comparison with untreated control patients suggested that basal LH did not completely return to prepubertal levels, whereas FSH levels were suppressed below prepubertal levels. Estradiol, FSH, and LH levels reached their nadir by 2 months; in contrast, mean serum levels of insulin-like growth factor I progressively declined from +0.57 +/- 0.19 SD score to -0.06 +/- 0.22 SD score at 24 months. Two girls were withdrawn from the study because of reactions at injection sites, with apparent sterile abscess formation in one patient. This study provides evidence that (1) long-term treatment with depot leuprolide is characterized by immediate and sustained laboratory and clinical suppression, (2) GnRH-stimulated LH and random FSH and estradiol concentrations are useful laboratory measures of efficacy, and (3) the progressive increase in predicted adult height is temporally associated with decreased serum levels of insulin-like growth factor I and striking deceleration of bone age advancement.
View details for Web of Science ID A1992JR92000026
View details for PubMedID 1403402
INSULIN-LIKE GROWTH-FACTORS (IGFS) - IMPLICATIONS FOR AGING PERGAMON-ELSEVIER SCIENCE LTD. 1992: 335-342
The insulin-like growth factors (IGF)-I and IGF-II are peptides with structural homology to insulin and potent mitogenic and anabolic actions in vitro and in vivo. IGF-I levels are growth hormone (GH)-dependent and vary strikingly with age. IGF-I levels are typically low in infancy and childhood, increase dramatically during puberty, and then gradually decline with advancing age. Whether age-associated changes in GH production or sex steroid secretion, or other unknown factors, cause diminished IGF production in the elderly remains to be determined. In the brain, IGF-II appears to be the most prevalent IGF, but a truncated form of IGF-I also has been recognized. IGF actions are mediated by binding to a family of receptors, which includes the insulin receptor, the structurally homologous type I IGF receptor, and the IGF-II/M-6P receptor, all of which are found in the central nervous system. Additionally, the IGFs bind with high affinity to a family of IGF-binding proteins (IGFBPs). Of the six known IGFBPs, IGFBP-2 appears to be the major one in the mammalian brain and is a major component of CSF. Immunoreactive IGFBP-2 has been identified in astrocytes, and its mRNA has been identified in fetal and adult brain and choroid plexus. The IGFBPs transport the IGFs in serum and other body fluids and appear to regulate IGF access to receptors. In vivo regulation of IGFBPs includes tissue-specific proteases, which cleave specific IGFBPs, altering their affinities for IGF peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1992JZ31000007
View details for PubMedID 1279737
INSULIN-LIKE GROWTH-FACTORS (IGFS) REDUCE IGF-BINDING PROTEIN-4 (IGFBP-4) CONCENTRATION AND STIMULATE IGFBP-3 INDEPENDENTLY OF IGF RECEPTORS IN HUMAN FIBROBLASTS AND EPIDERMAL-CELLS ENDOCRINOLOGY 1992; 130 (2): 985-993
Recent studies have provided a consensus that insulin-like growth factor-I (IGF-I) stimulates IGF-binding protein-3 (IGFBP-3) in vivo and in vitro. While it also appears well established that IGFBP-1 is inversely related to insulin concentrations, evidence regarding regulation of other IGFBP is inconclusive. Using immunoprecipitation and Western ligand blot, we have characterized the IGFBPs released into conditioned medium (CM) by cells from the adult human fibroblast cell line N3652 and the human epidermal squamous cell carcinoma line SCL-1. N3652 cells expressed IGFBP-3, IGFBP-2, a 24-kilodalton (kDa) IGFBP presumed to be IGFBP-4, and IGFBPs at 30 and 28 kDa. SCL-1 expressed IGFBP-3 and a putative IGFBP-4, with intermediate bands at 34 and 30 kDa. As determined by ligand blot of CM from confluent cells 72 h after the addition of peptides to serum-free medium, IGF-I and IGF-II potently stimulated IGFBP-3 in both cell lines, but otherwise IGFBP regulation in the two cells diverged. In N3652 cells, IGFBP-3 concentrations in CM increased to 700% and 800% of basal levels in the presence of IGF-I and IGF-II (at 100 ng/ml; n = 5 experiments), respectively. IGFBP-3 was not affected by insulin up to 10 micrograms/ml. In contrast, IGFBP-4 levels were diminished 54% and 73% by 100 ng/ml IGF-I and IGF-II, respectively, with no response to insulin. In SCL-1 cells, IGF-I and IGF-II were virtually identical in stimulating a mean 200% increase in IGFBP-3 (n = 5 experiments). Insulin was less potent, but caused a significant stimulation of IGFBP-3 levels. IGF-I, IGF-II, and insulin all stimulated an approximately 50% increase in IGFBP-4 concentrations. To test the hypothesis that IGF-induced alterations in IGFBP-3 and IGFBP-4 concentrations were regulated via the type 1 IGF receptor, we attempted to block IGFBP changes with type 1 IGF receptor antibody alpha IR-3 and to induce IGFBP changes with an IGF-II analog, [Leu27]IGF-II, with little affinity for the type 1 receptor. alpha IR-3 failed to block either the IGF-induced rise in IGFBP-3 in each cell line or the decline in IGFBP-4 in N3652 CM. [Leu27]IGF-II was as potent as IGF-II or IGF-I in inducing changes in IGFBP-3 and IGFBP-4 concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
View details for Web of Science ID A1992HH37100055
View details for PubMedID 1370799
HUMAN LEUKEMIC T-LYMPHOBLASTS AND B-LYMPHOBLASTS PRODUCE INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-2 AND PROTEIN-4 ACTA ENDOCRINOLOGICA 1991; 124 (6): 707-714
The production of insulin-like growth factors and insulin-like growth factor binding proteins by twelve human leukemic lymphoblast cell lines was evaluated by radioimmunoassay, affinity cross-linking, ligand blot, and immunoprecipitation of conditioned media. In all cell lines, detectable IGF-I and IGF-II levels were less than 0.1 micrograms/l and less than 0.3 micrograms/l, respectively. IGF binding proteins were identified in 6/12 of the lymphoblast cell lines studied. A pair of IGF binding proteins at 31 and 33 kD, immunoprecipitated with an antibody recognizing IGF binding protein 2 but not by an IGF binding protein 3 antibody, was produced by both T and B cells. A 24 kD IGF binding protein, presumably IGF binding protein 4, since it was not recognized by the antibodies for IGF binding proteins 1, 2, and 3, was produced by B cell precursor cells and faintly by one T cell line. These IGF binding proteins were not altered by deglycosylation. Neither IGF binding protein 1 nor IGF binding protein 3 was identified in any of the conditioned media. We speculate that local production of IGF binding proteins 2 and 4 regulates access of the IGFs to lymphoblasts and to hematopoietic precursors in general.
View details for Web of Science ID A1991FV71200015
View details for PubMedID 1712529
EFFICACY OF DEPOT LEUPROLIDE ACETATE IN THE TREATMENT OF CENTRAL PRECOCIOUS PUBERTY NATURE PUBLISHING GROUP. 1991: A83-A83
INSULIN-LIKE GROWTH-FACTOR RECEPTORS SCANDINAVIAN UNIVERSITY PRESS. 1991: 116-123
INSULIN-LIKE GROWTH-FACTORS ARE MITOGENIC FOR HUMAN KERATINOCYTES AND A SQUAMOUS-CELL CARCINOMA JOURNAL OF INVESTIGATIVE DERMATOLOGY 1991; 96 (1): 104-110
Normal adult human keratinocytes in monolayer culture and SCL-1, a skin-derived squamous-cell carcinoma cell line, were investigated for the expression of receptors for insulin-like growth factors (IGF) and insulin. As demonstrated by affinity crosslinking, radiolabeled IGF-1, IGF-2, and insulin bound specifically to both cell types. Each cell expressed type I IGF receptors, with affinity for IGF-1 greater than IGF-2 much greater than insulin. Insulin receptors, with highest affinity for insulin, were also present on both cells. However, keratinocytes and SCL-1 cells differed in 125I-IGF-2 binding. 125I-IGF-2-bound to both type I and type II IGF receptors in normal keratinocytes, but bound predominantly to membrane-associated IGF binding proteins in SCL-1. IGF-1 was slightly more potent than IGF-2 in stimulating growth of both keratinocytes and SCL-1 cells. In keratinocytes, concentrations of IGF-1 ranging from 5-100 ng/ml, and of IGF-2 from 50-100 ng/ml, resulted in a significant increase in cell number. At the maximum dose of 100 ng/ml, either IGF-1 or IGF-2 caused a 2.3-times increase in cell number. In SCL-1 cells, IGF-1 was more potent than IGF-2 or insulin at lower concentrations, but either IGF-1 or IGF-2 at the maximal concentration of 333 ng/ml stimulated a 4.7-times increase in thymidine incorporation. The stimulatory effect of insulin in SCL-1 was 10-50 times less potent than that of the IGF. The effect of either IGF on SCL-1 was completely inhibited by the type I IGF receptor antibody alpha IR-3, suggesting that both IGFs are mitogenic through the type I IGF receptor. Insulin action was partially blocked by alpha IR-3, suggesting that insulin can act through both the insulin and type I IGF receptors. It thus appears that IGF-1 and IGF-2 are mitogens for normal and transformed human keratinocytes and that their actions are primarily mediated through the type I IGF receptor, whereas insulin is a mitogen through both the IGF-1 receptor and the insulin receptor.
View details for Web of Science ID A1991ET57300019
View details for PubMedID 1846163
LONG-ACTING LUTEINIZING RELEASING-FACTOR (LRF) ANALOG FOR CENTRAL PRECOCIOUS PUBERTY NATURE PUBLISHING GROUP. 1990: A82-A82
EFFECT OF ESTROGEN ON GROWTH-HORMONE CONCENTRATIONS FOLLOWING STIMULATION WITH CLONIDINE NATURE PUBLISHING GROUP. 1990: A88-A88
SQUAMOUS-CELL CARCINOMA-CELLS DERIVED FROM SKIN EXPRESS BIOLOGICALLY-ACTIVE INSULIN-LIKE GROWTH-FACTOR RECEPTORS AND IGF BINDING-PROTEINS SLACK INC. 1989: A234-A234
INSULIN AND INSULIN-LIKE GROWTH-FACTORS IN COMMON ACUTE LYMPHOBLASTIC-LEUKEMIA CELL-LINES SLACK INC. 1989: A193-A193
HYPERALPHALIPOPROTEINEMIA, BIRTH TO AGE 2 YEARS PEDIATRIC RESEARCH 1981; 15 (1): 66-69
Interrelationships of high-density lipoprotein cholesterol (C-HDL) with total plasma cholesterol (TC), triglyceride, and low-density lipoprotein cholesterol, as well as longitudinal maintenance of C-HDL rank order (tracking) from birth to age 2 years were assessed in 76 hypercholesterolemic neonates (cord blood, TC greater than 95 mg/dl) with focus upon 34 hyperalphalipoproteinemic neonates who had cord blood C-HDL greater than 61 mg/dl, greater than or equal to the 99th percentile. Cord blood C-HDL correlated closely (P less than 0.01) with C-HDL at 6, 12, and 18 to 24 months (r = 0.32, 0.49, and 0.39, respectively). C-HDL levels at 12 months and 18 to 24 months were closely associated (r = 0.68 and P less than 0.01). C-HDL at birth, 6, and 12 months correlated positively (P less than 0.01) with TC levels (r = 0.28, 0.30, and 0.36, respectively). Conversely, C-HDL at birth, 6 and 12 months correlated inversely with TG (P less than 0.01) (r = -0.41, -0.40, and -0.49, respectively). At birth and at 18 to 24 months, C-HDL correlated inversely (P less than 0.05) with C-LDL (r = -0.36 and -0.31, respectively). Of neonates having cord blood C-HDL in the highest quartile, 38, 56, and 60%, respectively at ages 6, 12, and 18 to 24 months retained C-HDL levels in the highest quartile; 56, 75, and 70%, respectively, retained C-HDL levels greater than the 50th percentile. Of 13 neonates having the highest initial cord blood C-HDL levels, cord blood C-HDL greater than or equal to 69 mg/dl, nine had one or more C-HDL values greater than 70 mg/dl (the 90th percentile for childhood), throughout the 12- to 60-month follow-up period. Moreover, where more than one follow-up measurement was available, there was relative stability of elevated C-HDL measurements. Many infants with cord blood hyperalphalipoproteinemia are likely to have persistent elevations of C-HDL at ages 1 and 2 years. If they maintain elevated C-HDL into adulthood, they may, speculatively, be at reduced risk for coronary heart disease, given the strong inverse association of C-HDL with coronary heart disease.
View details for Web of Science ID A1981KY79100016
View details for PubMedID 7208170