Endocrinologist (diabetes, hormones), Pediatricians, Pediatric Specialist
31 years of experience

Accepting new patients
Pfizer Pharmaceuticals
235 E 42nd St
Murray Hill, New York, NY 10017
Locations and availability (6)

Education ?

Medical School
Universidad Catolica De Cordoba (1979)
Foreign school

Awards & Distinctions ?

Hormone Foundation

Affiliations ?

Dr. Cara is affiliated with 1 hospitals.

Hospital Affilations



  • Henry Ford Hospital
    2799 W Grand Blvd, Detroit, MI 48202
    • Currently 4 of 4 crosses
    Top 25%
  • Publications & Research

    Dr. Cara has contributed to 32 publications.
    Title Glimepiride Versus Metformin As Monotherapy in Pediatric Patients with Type 2 Diabetes: a Randomized, Single-blind Comparative Study.
    Date June 2007
    Journal Diabetes Care

    To compare the efficacy and safety of glimepiride versus metformin in pediatric subjects with type 2 diabetes inadequately controlled with diet and exercise alone or oral monotherapy.

    Title Type 2 Diabetes and the Metabolic Syndrome in Children and Adolescents.
    Date August 2006
    Journal Current Diabetes Reports

    The prevalence rates of obesity, metabolic syndrome, and type 2 diabetes in children are increasing at an alarming rate. The potential impact of these conditions on the individual, the family, and society, especially in regard to the costs and utilization of health care resources, are very serious. Strategies aimed at reducing caloric intake, increasing caloric expenditure through regular exercise, and treating cardiovascular risk factors and type 2 diabetes early and aggressively are necessary to meet the challenges they impose.

    Title Growth Hormone Therapy of Turner Syndrome: the Impact of Age of Estrogen Replacement on Final Height. Genentech, Inc., Collaborative Study Group.
    Date August 2000
    Journal The Journal of Clinical Endocrinology and Metabolism

    Clinical trials of recombinant human GH therapy in Turner syndrome that began more than a decade ago show that GH accelerates the linear growth rate. Several studies indicate that final height is also improved, although the magnitude of the increase has been debated. The age at which feminization is induced could be an important factor in determining the patient's ultimate growth response. To test this, 60 patients from a large (n = 117), previously unreported, clinical trial of GH treatment were randomly assigned to begin conjugated estrogens at either 12 or 15 yr of age. The 60 patients were all less than 11 yr of age at entry (mean, 9.5 yr) and received 0.375 mg/kg x week of GH for nearly 6 yr on a daily or three times weekly regimen. Height gain was calculated by comparing the study patients' final or near final heights to their pretreatment projected heights as well as to those of a separate set of age-matched, historical control patients. Patients in whom estrogen treatment was delayed until age 15 yr gained an average of 8.4 +/- 4.3 cm over their projected height, whereas those starting estrogen at 12 yr gained only 5.1 +/- 3.6 cm, on the average (P < 0.01). Analysis of the interval data showed that growth was stimulated for approximately 2 yr after estrogen initiation, but then declined in association with bone age advancement. Patients who were older than 11 yr at entry (n = 57) all initiated estrogen 1 yr after beginning GH and showed a mean gain in adult height of 4.7 cm, similar to those given estrogen at age 12 yr. Multivariate analysis revealed that the number of years of GH therapy before estrogen treatment was a strong factor in predicting height gained, indicating that the timing of estrogen introduction is an important determinant of final height in this cohort of GH-treated patients with Turner syndrome matched for baseline age and other characteristics.

    Title Growth Hormone Therapy of Turner's Syndrome: Beneficial Effect on Adult Height.
    Date March 1998
    Journal The Journal of Pediatrics

    OBJECTIVE: To carry out a multicenter, prospective, randomized trial of human growth hormone (GH), alone or in combination with oxandrolone (OX), in patients with Turner's syndrome (TS). METHODS: In an initial phase lasting 12 to 24 months, 70 girls with TS, verified by karyotype, were randomly assigned to one of four groups: (1) observation, (2) OX, (3) GH, or (4) GH plus OX. After completion of the first phase, group 3 subjects continued to receive GH only. All other subjects were treated with GH plus OX. Subjects were followed up until attainment of adult height and/or cessation of treatment. Data from this trial were compared with growth characteristics of 25 American historical subjects with TS (matched for age, height, parental target height, and karyotype) who never received either GH or androgens. RESULTS: Of the 70 subjects enrolled, 60 completed the clinical trial. The 17 subjects receiving GH alone all completed the trial and reached a height of 150.4+/-5.5 cm (mean +/- SD), 8.4+/-4.5 cm taller than their mean projected adult height at enrollment (95% confidence interval [CI]: 6.3 to 10.6 cm). The 43 subjects receiving GH plus OX attained a mean height of 152.1+/-5.9 cm, 10.3+/-4.7 cm taller than their mean projected adult height (95% CI: 8.9 to 11.7 cm). The historical control subjects had a mean adult height of 144.2+/-6.0 cm, precisely matching their original projected adult height of 144.2+/-6.1 cm. CONCLUSIONS: GH, either alone or in combination with OX, is capable of stimulating short-term growth and augmenting adult height in girls with TS. With early diagnosis and initiation of treatment, an adult height of more than 150 cm is a reasonable goal for most girls with TS.

    Title Gonadotropin Releasing Hormone Agonist (nafarelin) Test to Differentiate Gonadotropin Deficiency from Constitutionally Delayed Puberty in Teen-age Boys--a Clinical Research Center Study.
    Date November 1995
    Journal The Journal of Clinical Endocrinology and Metabolism

    The objective of this study was to determine whether the hormonal response to a GnRH agonist (nafarelin) challenge differentiates hypogonadotropinism from delayed puberty as well as the sleep test does. We studied boys ages 13.25-17.6 yr with prepubertal constitutional delay of puberty (CDP, n = 11), prepubertal gonadotropin deficiency (GnD, n = 10), pubertal CDP (PCDP, n = 11) and partial GnD (PGnD, n = 2). These disorders were defined on the basis of the following independent criteria: CDP = isolated delayed puberty with documentation of subsequent pubertal progression; GnD = panhypopituitarism or anosmia with absence of subsequent pubertal progression; PCDP = isolated delayed puberty in an early pubertal child; and PGnD = arrest of puberty in boys with partial hypopituitarism. CDP was compared with GnD and PCDP was compared with PGnD by analysis of variance and two-tailed t tests. Each patient had a nafarelin test with measurement of LH, FSH, and testosterone responses at intervals after nafarelin administration. Most patients had a sleep test with measurement of LH and testosterone levels at intervals overnight. CDP and GnD patients could not be distinguished by pubertal staging criteria. All but 1 patient with CDP had an LH response higher than that of GnD patients 4 h postnafarelin (P = 0.003). An incremental response to nafarelin of LH (delta LH at 4 h) below 4.8 IU/L was the best discriminant; it distinguished GnD from CDP in 95% of the cases and PGnD from PCDP completely. During the sleep test, all patients with CDP and 2 of 8 with GnD exhibited a significant increase in plasma LH. An incremental increase in LH during sleep (mean LH asleep minus mean LH awake) of less than 0.35 IU/L, near the limit of sensitivity of the method, differentiated GnD from CDP similarly to the nafarelin test. We conclude that the LH response to nafarelin distinguished gonadotropin deficiency from constitutional delay of puberty as well as the sleep test did and with certain advantages. The diagnostic reliability of the GnRH agonist test deserves to be determined prospectively in teen-agers with isolated GnD and partial hypopituitarism.

    Title Insulin-like Growth Factors, Insulin-like Growth Factor Binding Proteins and Ovarian Androgen Production.
    Date December 1994
    Journal Hormone Research

    Increasing evidence indicates that the ovary contains an insulin-like growth factor (IGF) system complete with ligands, binding proteins, and receptors. Through their interaction with IGF receptors on theca-interstitial cell surface membranes, the ligands, IGF-I and IGF-II, synergize with luteinizing hormone (LH) to increase ovarian androgen production. The actions of these growth factors are modulated by intraovarian binding proteins, especially IGFBP-1, IGFBP-2, and IGFBP-3, that enhance or inhibit the biological actions of the IGFs. These observations suggest that the IGF system plays a role in normal ovarian function and in the pathophysiology of ovarian hyperandrogenism and polycystic ovary syndrome.

    Title Ovarian Hyperandrogynism As a Result of Congenital Adrenal Virilizing Disorders: Evidence for Perinatal Masculinization of Neuroendocrine Function in Women.
    Date December 1994
    Journal The Journal of Clinical Endocrinology and Metabolism

    Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.

    Title Importance of Receptor Occupancy, Concentration Differences, and Ligand Exchange in the Insulin-like Growth Factor I Receptor System.
    Date January 1994
    Journal Proceedings of the National Academy of Sciences of the United States of America

    We have investigated by use of placental membranes the mechanisms through which insulin-like growth factor I (IGF-I) comes to be associated with its alpha 2 beta 2 receptor heterotetramer. Our results suggest that (i) at low ligand concentrations, the formation and disruption of IGF-I--receptor complexes are consistent with ligand binding de novo to empty receptors but not with equilibria involving ligand dissociation; (ii) at higher ligand concentrations, rapid exchange arising from the formation and collapse of bis-liganded receptors leads to a transiently perturbed receptor state; (iii) these nonclassical IGF-I receptor interactions depend on close communication between the alpha beta halves of the alpha 2 beta 2 holo-IGF-I receptor; and (iv) related processes based on ligand exchange have the potential for serving as biological sensors of changes in ligand concentration, while ordinary binding processes serve as sensors of ligand concentrations themselves. A model is presented in which one or two molecules of ligand can be bound to an alpha 2 beta 2 IGF-I receptor heterotetramer, new ligand becomes associated with receptor by exchanging for a previously bound molecule of IGF-I, and fluctuating changes in free-ligand concentration might lead to enhanced IGF-I function.

    Title Growth Hormone in Adolescence. Normal and Abnormal.
    Date December 1993
    Journal Endocrinology and Metabolism Clinics of North America

    The adolescent growth spurt is one of the dramatic physical changes that accompanies pubertal development. The rate of growth during the adolescent growth spurt is greater than at any other time of life after infancy. In this article, the pathophysiology of normal adolescent growth is reviewed, factors that control growth in adolescence are addressed, and the growth hormone deficiency syndromes presenting in adolescence are discussed.

    Title Potential of Gonadotropin-releasing Hormone Agonists in the Diagnosis of Pubertal Disorders in Girls.
    Date November 1993
    Journal Clinical Obstetrics and Gynecology
    Title Growth Response of Children with Non-growth-hormone Deficiency and Marked Short Stature During Three Years of Growth Hormone Therapy.
    Date September 1993
    Journal The Journal of Pediatrics

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

    Title Maturation of Gonadotropin and Sex Steroid Responses to Gonadotropin-releasing Hormone Agonist in Males.
    Date March 1993
    Journal The Journal of Clinical Endocrinology and Metabolism

    We have previously demonstrated that a single dose of the GnRH agonist nafarelin stimulates both gonadotropin and sex steroid secretion in adult men and women. In order to define the maturational steps involved in this response, we tested the effect of nafarelin on LH, FSH, testosterone (T), and estradiol (E2) secretion over 24 h in four groups of males: prepubertal (P1; n = 4), early pubertal (P2; n = 8), and midpubertal boys (P3; n = 4) with variations in the timing of puberty, and normal young adult males (P4; n = 10). Nafarelin stimulated rapid gonadotropin release in all groups, but the pattern of LH response varied. In prepubertal and pubertal boys, LH levels peaked 3-4 h after nafarelin and declined by 50% or more at 24 h post nafarelin. By contrast, adults reached an initial LH peak at 1 h, and LH secretion was sustained with levels 24 h post nafarelin equivalent to those during the early response phase. Nafarelin stimulated T secretion in all groups, but the response was greatest in groups P3 and P4; the maximal incremental rise (delta) in T was 1.2 +/- 0.5, 4.4 +/- 1.0, 18.8 +/- 5.4, and 15.3 +/- 1.4 nmol/L in P1, P2, P3, and P4 males, respectively (analysis of variance: F = 14.4, P < 0.001). E2 concentrations increased much more in adults than in the other groups post nafarelin: delta E2 was 5.5 +/- 1.1, 22.1 +/- 14.7, 83.9 +/- 47.5, and 323.8 +/- 14.7 pmol/L in the P1, P2, P3, and P4 groups, respectively (F = 71.1, P < 0.001). Similarly, the delta E2/delta T ratio was significantly greater in adult males than in less mature males. This developmental pattern of response to nafarelin suggests that male pubertal maturation involves increase of the gonadotrope LH readily releasable and reserve pools. The dissociation of E2 from T responses to nafarelin during puberty suggests that aromatase activity does not fully mature in males until puberty is complete. These findings indicate that a single dose of the GnRH agonist nafarelin is a promising means of assessing the maturation of the pituitary-gonadal axis in males.

    Title Interactions of a Hybrid Insulin/insulin-like Growth Factor-i Analog with Chimeric Insulin/type I Insulin-like Growth Factor Receptors.
    Date March 1993
    Journal The Journal of Biological Chemistry

    We have examined, by use of a hybrid insulin/insulin-like growth factor-I analog and chimeric insulin/type I insulin-like growth factor receptors, the interplay between ligand and receptor structure in determining the affinity and specificity of hormone-receptor interactions in the insulin and insulin-like growth factor-I systems. Our findings, obtained through the study of radiolabeled peptide binding to detergent-solubilized full-length receptors and to soluble truncated receptors, show that (a) the two-chain hybrid analog exhibits significant cross-reactivity with both receptor systems, (b) the exchange of appropriate domains in chimeric receptors enhances the receptor binding affinity of the analog by 3.5-21-fold, and (c) the affinity of the hybrid analog for the chimeric receptors actually exceeds that of either natural insulin or natural insulin-like growth factor-I. We conclude that the specificity-conferring domains of the insulin and type I insulin-like growth factor receptors reside in different regions of a common binding site, and that the exchange of domains between pairs of related hormones and between pairs of related receptors can yield new ligand-receptor systems with significantly altered affinities and selectivities.

    Title Six-year Results of a Randomized, Prospective Trial of Human Growth Hormone and Oxandrolone in Turner Syndrome.
    Date August 1992
    Journal The Journal of Pediatrics

    Seventy girls with Turner syndrome, verified by karyotype, were randomly assigned to observation or treatment with human growth hormone (hGH), oxandrolone, or a combination of hGH plus oxandrolone for a period of 12 to 24 months, to assess the effect of treatment on growth velocity and adult height. Subsequently, all subjects received either hGH alone or hGH plus oxandrolone. Data are presented for 62 subjects treated for a period of 3 to 6 years. When compared with the anticipated growth rate in untreated patients, the growth rate after treatment with hGH, both alone and in combination with oxandrolone, showed a sustained increase for at least 6 years. Treatment is continuing in over half of the subjects; at present, 14 (82%) of 17 girls receiving hGH alone and 41 (91%) of 45 girls receiving combination therapy exceeded their expected adult heights. Thirty girls have completed treatment; mean height for these 30 patients is 151.9 cm, compared with their mean original projected adult height of 143.8 cm. We conclude that therapy with hGH, alone and in combination with oxandrolone, can result in a sustained increase in growth rate and a significant increase in adult height for most prepubertal girls with Turner syndrome.

    Title Height Prognosis of Children with True Precocious Puberty and Growth Hormone Deficiency: Effect of Combination Therapy with Gonadotropin Releasing Hormone Agonist and Growth Hormone.
    Date June 1992
    Journal The Journal of Pediatrics

    We evaluated height prognosis and therapeutic efficacy of long-term, combination therapy with gonadotropin releasing-hormone agonist and growth hormone (GH) in five children (three girls) with coexistent precocious puberty and GH deficiency. Their clinical characteristics and growth response were compared with those of 12 girls with idiopathic true precocious puberty and eight prepubertal GH-deficient children (one girl). Precocious GH-deficient subjects were older than the precocious GH-sufficient children (9.5 +/- 1.8 years vs 6.5 +/- 1.3 years; mean +/- SD), but bone ages were comparable (12 +/- 3.7 years vs 10 +/- 0.9 years); their chronologic age was similar to that of the prepubertal GH-deficient children (9.6 +/- 2.1 years), but bone age was significantly more advanced (6.9 +/- 2.3 years). The mean height velocity of the prepubertal GH-deficient children (3.8 +/- 1.5 cm/yr) was lower than that of the precocious GH-deficient subjects (6.7 +/- 1.6 cm/yr) and the precocious GH-sufficient children (9.5 +/- 2.9 cm/yr). Baseline adult height prediction z scores were significantly lower in the precocious GH-deficient children (-3.7 +/- 1.0) than in either the precocious GH-sufficient children (-2.2 +/- 1.0) or the prepubertal GH-deficient subjects (-1.5 +/- 0.8). During therapy with gonadotropin releasing-hormone agonist, growth rates slowed to an average of 3.7 cm/yr in the precocious GH-deficient children but increased after the addition of GH to 7.4 cm during the first year of combination therapy. After 2 to 3 years of combination therapy, height predictions increased an average of 10 cm, compared with an increase of 2.8 cm in the precocious GH-sufficient group treated with gonadotropin releasing-hormone agonist alone. We conclude that combination treatment with gonadotropin releasing-hormone agonist and GH improves the height prognosis of children with coexistent true precocious puberty and GH deficiency, but falls short of achieving normal adult height potential.

    Title Growth Hormone for Short Stature Not Due to Classic Growth Hormone Deficiency.
    Date January 1991
    Journal Pediatric Clinics of North America

    The advent of recombinant DNA technology has resulted in potentially unlimited supplies of growth hormone. Sufficient quantities are now available not only for the long-term, uninterrupted treatment of GH-deficient children but potentially for the treatment of non-GH-deficient patients with other short stature or growth attenuating disorders. Short-term studies have demonstrated an improvement in the growth rates of subjects with isolated short stature, Turner syndrome, and chronic renal failure; and additional studies are under way to assess the efficacy of GH therapy of other short stature syndromes. However, the long-term efficacy and possible adverse effects of GH treatment in these situations is not known. Until there has been more experience, GH deficiency should remain the primary indication for GH treatment. Growth hormone should not be considered routine therapy for other conditions associated with or resulting in short stature. However, research should continue in these areas to define which children may benefit from GH treatment.

    Title An Insulin-like Growth Factor I/insulin Hybrid Exhibiting High Potency for Interaction with the Type I Insulin-like Growth Factor and Insulin Receptors of Placental Plasma Membranes.
    Date November 1990
    Journal The Journal of Biological Chemistry

    We have prepared by semisynthetic methods a two-chain insulin/insulin-like growth factor I hybrid that contains a synthetic peptide related to residues 22-41 of insulin-like growth factor I linked via peptide bond to ArgB22 of des-octapeptide-(B23-B30)-insulin and have applied the analog to the analysis of ligand interactions with the type I insulin-like growth factor and insulin receptors of placental plasma membranes. Relative potencies for the inhibition of 125I-labeled insulin-like growth factor I binding to type I insulin-like growth factor receptors were 1.0:0.20:0.003 for insulin-like growth factor I, the hybrid analog, and insulin, respectively. Corresponding relative potencies for the inhibition of 125I-labeled insulin binding to insulin receptors were 0.007:0.28:1 for the three respective peptides. Additional studies identified that the hybrid analog interacts with only one of two populations of insulin-like growth factor I binding sites on placental plasma membranes and permitted the analysis of insulin-like growth factor I interactions with the separate populations of binding sites. We conclude that (a) des-octapeptide-(B23-B30)-insulin can serve well as a scaffold to support structural elements of insulin-like growth factor I and insulin necessary for high affinity binding to their receptors, (b) major aspects of structure relevant to the conferral of receptor binding affinity lie in the COOH-terminal region of the insulin B chain and in the COOH-terminal region of the insulin-like growth factor I B domain and in its C domain, and (c) the evolution of ligand-receptor specificity in these systems has relied as much on restricting interactions (through the selective introduction of negative structural elements) as it has on enhancing interactions (through the introduction of affinity conferring elements of structure).

    Title Preserving Adult Height Potential in Girls with Idiopathic True Precocious Puberty.
    Date October 1990
    Journal The Journal of Pediatrics

    We designed a prospective study of height potential in girls with idiopathic precocious puberty, comparing the presenting features of girls with and without evidence of reduced adult height potential. The 14 girls with impaired adult height prognoses (group 1) were reexamined after treatment with a gonadotropin releasing hormone agonist, nafarelin. The seven girls with the prognosis of unimpaired height (group 2) were followed without therapy. We found that the group could be distinguished at initial examination by the greater bone age/height age ratio of group 1 (mean +/- SEM: 1.4 +/- 0.06 vs 1.0 +/- 0.05; p less than 0.005) and by the greater difference between predicted height and target height in group 1. The mean predicted height in group 1 was significantly less than the mean target height (150.7 +/- 2.1 vs 165.4 +/- 3.0 cm; p less than 0.005), whereas the mean predicted and target heights in group 2 were similar (165.4 +/- 3.0 vs 164.3 +/- 2.1 cm). Initial estradiol levels were also greater in group 1 than in group 2 (21.6 vs 10.6 pg/ml; p less than 0.05), although this difference was not sustained during follow-up. In group 1, nafarelin therapy suppressed the pituitary-gonadal axis, and although there was a transient reduction in height potential in girls with the youngest bone ages during the first 6 months of therapy, 2 years of treatment slightly improved predicted heights from 150.7 +/- 2.1 to 152.7 +/- 2.0 cm (p less than 0.05). Height predictions also increased without therapy during the 2-year observation period in group 2, from 165.4 +/- 3.0 to 168.7 +/- 4.1 cm (p less than 0.05). Our data indicate that gonadotropin releasing hormone agonist therapy preserves height potential in girls with an initially impaired height prognosis, and that height potential is preserved without therapy in those with a good initial height prognosis.

    Title Insulin-like Growth Factor-i Enhances Luteinizing Hormone Binding to Rat Ovarian Theca-interstitial Cells.
    Date September 1990
    Journal The Journal of Clinical Investigation

    We tested the hypothesis that insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production by increasing theca-interstitial cell luteinizing hormone (LH) binding affinity and/or binding capacity. We then investigated the role of transcriptional and translational events in mediating these actions of IGF-I. LH bound to saturable, high affinity binding sites on rat ovarian theca-interstitial cells. Preincubation with LH produced a decrease in LH binding capacity with no effect on LH binding affinity. Treatment with IGF-I, both in the absence and presence of LH, increased LH binding capacity 1.5- to 2-fold with no change in LH binding affinity. Androgen production was increased progressively by LH, suggesting that LH-stimulated steroidogenesis is not tightly coupled to LH receptor downregulation. IGF-I increased androgen synthesis in proportion to its upregulation of LH binding capacity. Transcriptional inhibition with dichlorobenzimidazole riboside inhibited the IGF-I-mediated increase in LH binding capacity but had no effect on androgen production. Translational inhibition with cycloheximide inhibited both the IGF-I-mediated increase in LH binding and stimulation of androgen synthesis. We conclude that IGF-I increases theca-interstitial cell LH binding capacity and reverses the LH-induced downregulation of LH binding sites. The enhancement of LH binding by IGF-I is compatible with transcriptional mediation whereas the effect of IGF-I on androgen synthesis appears to be mediated by a direct effect of the peptide on the translational process(es) involved in steroidogenesis.

    Title Dysregulation of Cytochrome P450c 17 Alpha As the Cause of Polycystic Ovarian Syndrome.
    Date June 1990
    Journal Fertility and Sterility

    Polycystic ovarian syndrome (PCOS) appears to be due to a previously unrecognized type of steroidogenic abnormality, one in which hyperandrogenism arises from a regulatory abnormality (dysregulation) rather than from enzyme deficiency. It appears that PCOS typically arises from masculinized regulation of the androgen-forming enzyme (cytochrome P450c17 alpha) within ovarian thecal cells. This may arise by either excessive stimulation by luteinizing hormone (LH) or by escape from desensitization to LH. We review evidence which is compatible with the concept that the latter situation may result from an intrinsic intraovarian flaw in the paracrine feedback mechanism by which thecal androgen biosynthesis is inhibited and that coexistent adrenal 17-ketosteroid hyper-responsiveness to corticotropin (ACTH) may be due to a similar type of dysregulation of adrenocortical P450c17 alpha.

    Title Use of Nafarelin for Testing Pituitary-ovarian Function.
    Date March 1990
    Journal The Journal of Reproductive Medicine

    A single dose of nafarelin can test pituitary-ovarian function from infancy through maturity.

    Title A New Test of Combined Pituitary-testicular Function Using the Gonadotropin-releasing Hormone Agonist Nafarelin in the Differentiation of Gonadotropin Deficiency from Delayed Puberty: Pilot Studies.
    Date November 1989
    Journal The Journal of Clinical Endocrinology and Metabolism

    There is evidence that the capacity to synthesize gonadotropins is less in teenage boys with gonadotropin deficiency (GD) than in those with constitutional delay of puberty (DP). We hypothesized that this might predispose the latter group to have a greater pituitary-testicular response to the potent long-acting GnRH agonist nafarelin. We evaluated GD patients 14.3-24.0 yr of age (n = 8) and prepubertal DP boys 14.8-17.6 yr of age (n = 3). In most subjects the response to nafarelin was compared to that of frequent nocturnal blood sampling for LH and testosterone levels. All subjects received a single dose of nafarelin (1.0 micrograms/kg, sc), and blood was then sampled at 0.5- to 4.0-h intervals for 24 h. Patients with GD could not be distinguished from those with DP by pubertal staging criteria or by baseline values of LH, FSH, or testosterone. Patients with GD exhibited no rise in plasma LH levels during sleep, in contrast to those with DP. All GD patients had LH and FSH responses distinctly less than those of the DP group between 3-24 h postnafarelin. The peak incremental responses of GD and DP to nafarelin were, respectively: LH, 5.5 +/- 2 3 (+/- SEM and 77.2 +/- 8.6 IU/L (P less than 0.02); FSH, 2.7 +/- 1.2 and 9.4 +/- 0.8 IU/L (P less than 0.005). Testosterone peak responses were lower as well (0.26 +/- 0.2 vs 1.6 +/- 0.5 nmol/L, P = 0.05). This pilot study suggests that the response to a single test dose of nafarelin distinguishes GD from DP in the teenage years as well as does measurement of nocturnal LH levels. The testosterone response to the GnRH agonist adds a new dimension to GnRH testing. Nafarelin also allows assessment of the bioactivity of endogenous gonadotropin, is a more potent stimulus of pituitary-testicular function than endogenous GnRH secretion, and is more cost-effective than nocturnal sampling.

    Title Growth Hormone Deficiency Impedes the Rise in Plasma Insulin-like Growth Factor I Levels Associated with Precocious Puberty.
    Date August 1989
    Journal The Journal of Pediatrics

    We tested the hypothesis that growth hormone (GH) mediates the rise in insulin-like growth factor I (IGF-I) concentrations in children with precocious puberty. We studied three groups of patients. Group 1 included six children with GH deficiency and precocious puberty (precocious GH-deficient); group 2 included 10 GH-sufficient patients with idiopathic true precocious puberty (precocious GH-sufficient); and group 3 included 9 prepubertal children with GH deficiency (prepubertal GH-deficient). Growth rates, pubertal status, and plasma IGF-I concentrations were determined at regular intervals. The precocious children with GH deficiency had a mean (+/- SD) growth rate of 7.2 +/- 2.1 significantly below that of the precocious GH-sufficient patients (10.5 +/- 2.5 cm/yr, p less than 0.05) but above that of the prepubertal GH-deficient children (3.9 +/- 1.4 cm/yr, p less than 0.05). The mean IGF-I concentration in the precocious GH-deficient children was 0.77 +/- 0.39 U/ml, significantly lower than the mean level of 2.2 +/- 0.67 U/ml in the precocious GH-sufficient patients (p less than 0.01). However, precocious GH-deficient patients had significantly higher IGF-I values than the prepubertal GH-deficient children (0.24 +/- 0.10 U/ml, p less than 0.05). IGF-I values did not rise with the onset of precocious puberty in four of the precocious GH-deficient children evaluated before and after the development of precocious puberty. However, three patients who began GH treatment did have a rise in plasma IGF-I concentrations to levels of 1.2, 3.4, and 3.7 U/ml, respectively. These findings are compatible with the concept that sex steroids increase IGF-I levels in precocious puberty primarily by increasing GH production. A small but direct effect of sex steroids on IGF-I production may also exist. The onset of precocious puberty in children with organic GH deficiency may mask the abnormal growth pattern of these children and delay diagnosis; determinations of plasma IGF-I concentrations may be helpful in assessing the GH status of these patients.

    Title A Monoclonal Antibody to the Type 1 Insulin-like Growth Factor and Insulin Receptors Stimulates Deoxyribonucleic Acid Synthesis in Human and Murine Fibroblasts.
    Date September 1988
    Journal Endocrinology

    Insulin-like growth factor I (IGF-I) and insulin are polypeptide hormones that stimulate their cellular responses by binding to specific cell membrane receptors. These receptors, while chemically distinct, have similar structural and functional characteristics. This manuscript describes the production and characterization of a monoclonal antibody that binds to both type I IGF and insulin receptors. This antibody did not inhibit hormone binding to either receptor type, but stimulated DNA synthesis in both human and murine fibroblasts. Ten BALB/c-BYJ mice were immunized with human placental membrane fragments, and their splenic lymphocytes were fused with SP2 AG0 mouse myeloma cells. Of approximately 3000 hybridoma clones thus obtained, 1 viable clone, designated V3,8 D7, was found to produce an antibody directed against the type I IGF receptor. Solubilized radiolabeled placental membranes immunoprecipitated with affinity-purified antibody and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions revealed bands with relative molecular masses corresponding to the nonreduced intact receptor (approximately 350 x 10(3], the alpha-subunit (130-140 x 10(3], and the beta-subunit (90 x 10(3] of the type I IGF receptor. Clonal supernatant and affinity-purified antibody precipitated solubilized receptors affinity labeled with [125I]IGF-I. Antibody V3,8 D7 also precipitated solubilized placental membranes affinity labeled with [125I]insulin. However, solubilized receptors affinity purified by the monoclonal antibody bound IGF-I much better than insulin, suggesting that this antibody has a higher affinity for the type I IGF receptor than for the insulin receptor. Affinity-purified antibody did not inhibit the binding of IGF-I or insulin to receptors on human placental membranes, suggesting that it is directed against a site on the type I IGF and insulin receptor not involved in hormone binding. However, affinity-purified monoclonal antibody stimulated DNA synthesis in human GM 498 and murine BALB/c-3T3 clone A 31 fibroblasts, as determined by [3H]thymidine incorporation. The combination of IGF-I and affinity-purified antibody did not increase thymidine incorporation above levels observed with either substrate alone, suggesting that these factors may be operating through a common mechanism. These results suggest that antibody V3,8 D7 can stimulate receptor responses by binding to a site on the type I IGF and/or insulin receptors that is not involved in hormone binding. These data support the concept that hormone receptors themselves possess the biological information required for stimulating specific cellular responses.

    Title Insulin-like Growth Factor I and Insulin Potentiate Luteinizing Hormone-induced Androgen Synthesis by Rat Ovarian Thecal-interstitial Cells.
    Date August 1988
    Journal Endocrinology

    We tested the hypothesis that insulin-like growth factor I (IGF-I) and insulin play a role in androgen production by rat ovarian thecal-interstitial cells. Collagenase/DNase-dispersed rat ovarian thecal-interstitial cells obtained from immature hypophysectomized Sprague-Dawley rats were cultured at a concentration of 10(6) cells/ml in serum-free medium in the presence of increasing concentrations of LH, IGF-I, or insulin. The medium was replaced every 48 h, and the androsterone concentration in the culture supernatants was used as an index of androgen production. In the absence of added hormones (control) androsterone levels were consistently less than 0.1 ng/ml. Increasing concentrations of LH stimulated androsterone synthesis in a dose-dependent manner. IGF-I, in the absence of LH, did not significantly increase androsterone levels above control values. However, when combined with 10 ng/ml LH, IGF-I increased androsterone synthesis above levels seen with LH alone in a dose-related fashion: for example, the peak androsterone levels seen with LH and 100 ng/ml (13 nM) IGF-I at 96 h of culture were significantly greater than the peak level seen with 10 ng/ml LH alone (302 +/- 71 vs. 17 +/- 7 ng/ml; P less than 0.0125). Similarly, while insulin alone did not increase androsterone synthesis above control values, androsterone concentrations were increased by insulin in combination with 10 ng/ml LH; a peak value of 240 +/- 67.7 ng/ml was observed at 96 h of culture with 100 ng/ml (18 mM) insulin (P less than 0.025 vs. LH alone) Androsterone levels were slightly less with insulin than with IGF-I, but this difference was not significant. The combination of IGF-I and insulin did not increase levels of androsterone synthesis above those observed with each hormone alone. IGF-I bound to a high affinity binding site on ovarian cell monolayer cultures with an apparent binding affinity of 1.3 x 10(-9) M. Insulin also competed for binding with radiolabeled IGF-I in a dose-dependent manner, but the affinity of insulin was approximately 500-fold less; half-maximal inhibition of [125I] IGF-I binding occurred with an insulin concentration of approximately 300 nM (or approximately 1700 ng/ml). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of thecal-interstitial cell monolayers affinity labeled with radiolabeled IGF-I in the absence and presence of unlabeled hormone revealed proteins with characteristics of type I IGF receptors. Affinity labeling to a protein of a relative molecular mass of approximately 45,000 was also noted, probably representing IGF carrier proteins synthesized by thecal-interstitial cell monolayers.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Structural Determinants of Ligand Recognition by Type I Insulin-like Growth Factor Receptors: Use of Semisynthetic Insulin Analog Probes.
    Date June 1988
    Journal Endocrinology

    We undertook a systematic analysis of the structural determinants necessary for ligand recognition by the type I insulin-like growth factor (IGF) receptor by investigating the binding of semisynthetic insulin analogs to IGF receptors from human placental cell membrane fragments. Analogs were prepared by synthetic and semisynthetic methods. Three groups of insulin analogs were synthesized: the first group contained insulin analogs modified at the amino-terminal position of the insulin A chain and included acetyl-insulin and human proinsulin; the second group included analogs in which B chain residues B26-B30 [despentapeptide insulin (DPI)], B25-B30 (deshexapeptide insulin), and B24-B30 (desheptapeptide insulin) were removed; the third group contained insulin analogs in which B chain residues B26-B30 were removed (DPI) and phenylalanine(B25) substituted with other amino acids, including alanine, serine, leucine, and tyrosine. Half-maximal inhibition of binding of radiolabeled IGF-I to placental cell membrane fragments was used as an index of relative binding affinity (K1/2). To determine further if semisynthetic insulin analogs bound to the type I IGF receptor, placental membrane fragments were affinity labeled with radiolabeled IGF-I in the presence and absence of submaximal concentrations of unlabeled hormone, insulin, or semisynthetic analogs, and the labeled proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Insulin had a 500 times lower affinity for the type I IGF receptor than IGF-I [K1/2 = 140 +/- 69 nM (mean +/- SD)] whereas proinsulin and acetyl insulin had a more than 100 times lower affinity than insulin for this receptor type. Removal of insulin B chain amino acid residues 26-30 (DPI) did not negatively affect the binding of the insulin-derived peptide and actually increased the apparent affinity of ligand-receptor association approximately 2-fold. However, further removal of phenylalanine(B25) (deshexapeptide insulin) and phenylalanine(B24) (desheptapeptide insulin) decreased the binding of ligand to the type I IGF receptor progressively by several orders of magnitude. Substitution of phenylalanine(B25) of DPI with tyrosine, a substitution that actually increased the homology of this analog to IGF-I, resulted in a 4- to 5-fold increase in the relative apparent affinity of the analog for the type I IGF receptor (K1/2 = 31 +/- 4 nM). On the other hand, substitution of phenylalanine(B25) with alanine, serine, and leucine decreased the relative apparent binding affinity approximately 2- to 8-fold.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Quantitation of Urinary Somatomedin-c and Growth Hormone in Preterm and Fullterm Infants and Normal Children.
    Date April 1988
    Journal The Journal of Clinical Endocrinology and Metabolism

    Urinary GH and somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) excretion were measured in 12-h urine collections obtained from 43 infants (27 stable preterm infants and 16 healthy fullterm infants) and 31 normal children, aged 3-17 yr. Urinary Sm-C/IGF-I was excreted as the free hormone, since no binding of radiolabeled Sm-C/IGF-I to any urine protein with a mol wt similar to those described for plasma Sm-C/IGF-I-binding proteins was found. The preterm infants excreted significantly more urinary GH [13.5 +/- 2.1 (+/- SE) ng/kg.12 h] than either the fullterm infants (5.3 +/- 1.6 ng/kg.12h) or the children (0.27 +/- 0.02 ng/kg.12 h; P less than 0.01). The mean urinary Sm-C/IGF-I excretion in the preterm infants (98.9 +/- 7.5 mU/kg.12 h) was comparable to that in fullterm infants (87.6 +/- 9.7 mU/kg.12 h); both groups excreted significantly more urinary Sm-C/IGF-I than children (28.4 +/- 2.1 mU/kg.12 h; P less than 0.01). The group differences were similar when the results were expressed in terms of creatinine excretion. Urinary GH excretion correlated positively with urinary Sm-C/IGF-I excretion (r = 0.68). The higher output of these peptides in rapidly growing infants and their positive correlation in urine provide additional support for the Sm hypothesis.

    Title A Longitudinal Study of the Relationship of Plasma Somatomedin-c Concentration to the Pubertal Growth Spurt.
    Date May 1987
    Journal American Journal of Diseases of Children (1960)

    Cross-sectional studies from our institutions (Wyler Children's Hospital, Chicago, and Children's Hospital of Philadelphia) and others have shown that plasma somatomedin-C (Sm-C) concentrations rise during puberty. To determine the relationship between rising plasma Sm-C levels and the growth spurt at puberty, we undertook a longitudinal study of 11- to 18-year-old children. Twelve male and eight female subjects were followed up on a yearly basis for two to seven years (mean, 4.4 years). Height velocity, plasma Sm-C concentrations, and stage of sexual development were determined during each visit. All patients progressed normally in puberty during the study. The plasma Sm-C level rose during early puberty in each child and reached a maximal level of at least 2 U/mL In midpuberty, approximately one year after the attainment of peak height velocity. Maximal plasma concentrations of Sm-C were similar in male (3.5 +/- 0.71, mean +/- SEM) and female (3.5 +/- 1.46) subjects. Plasma Sm-C levels subsequently decreased slowly but remained above normal adult values for as long as four years after peak height velocity was reached. Plasma Sm-C concentrations increased steadily with increasing height velocity until peak height velocity was attained with a mean rise of approximately 0.5 U for each centimeter per year increase in height velocity. Since Sm-C levels remained elevated while height velocity decreased, there was no significant correlation between Sm-C levels and height velocity throughout puberty. These results suggest that caution is required in interpreting Sm-C concentrations during puberty; while normal pubertal levels may be in the acromegalic range for adults, a plasma Sm-C level of less than 1 U/mL in early puberty or less than 1.5 U/mL during middle to late puberty must be considered subnormal.

    Title Somatomedin-c/insulin-like Growth Factor-i As a Modulator of Growth During Childhood and Adolescence.
    Date November 1986
    Journal Hormone Research

    Normal growth during childhood and adolescence is a complex process which requires the participation of a number of hormones and growth factors. Sm-C/IGF-I plays a central role in this process, with variations in both its serum concentration and the cellular responsiveness to it being important mechanisms regulating growth.

    Title The Prolactin Response to Thyrotropin-releasing Hormone Does Not Distinguish Teenaged Males with Hypogonadotropic Hypogonadism from Those with Constitutional Delay of Growth and Development.
    Date December 1985
    Journal The Journal of Clinical Endocrinology and Metabolism

    We attempted to confirm the results of a previous study in which patients with hypogonadotropic hypogonadism (HH) could be readily distinguished from normal adolescents with constitutional delay of growth and development (CDGD) by their lower serum PRL responses to TRH. We compared the PRL responses to TRH of 13 teenaged males with HH to those of 14 teenaged males with CDGD. Although the mean maximum serum PRL concentration after TRH in HH patients (29.5 ng/ml) was significantly less (P less than 0.05) than that in the CDGD subjects (41.1 ng/ml), there was considerable overlap between the 2 groups. Seven of the 13 HH patients had peak serum PRL concentrations in response to TRH that were greater than 25 ng/ml, the lowest value in the CDGD subjects. These results suggest that a normal PRL response to TRH in a male who has delayed puberty does not exclude the diagnosis of HH, but that a subnormal response probably does support that diagnosis.

    Title Elevated 17-hydroxyprogesterone and Testosterone in a Newborn with 3-beta-hydroxysteroid Dehydrogenase Deficiency.
    Date September 1985
    Journal The New England Journal of Medicine
    Title Ease of Use and Preference for a New Disposable Self-injection Pen Compared with a Reusable Pen for Administering Recombinant Human Growth Hormone: A Multicenter, 2-month, Single-arm, Open-label Clinical Trial in Patient-caregiver Dyads.
    Journal Clinical Therapeutics

    improved ease of use of drug-delivery devices may enhance compliance. Development of an easier-to-use device for administration of recombinant human growth hormone (rhGH) may thus be beneficial for patients and their caregivers.

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