Insulin-like growth factor-I enhances luteinizing hormone binding to rat ovarian theca-interstitial cells.

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.

Insulin-like growth factor I and insulin potentiate luteinizing hormone-induced androgen synthesis by rat ovarian thecal-interstitial cells.

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)

A monoclonal antibody to the type 1 insulin-like growth factor and insulin receptors stimulates deoxyribonucleic acid synthesis in human and murine fibroblasts.

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.

Structural determinants of ligand recognition by type I insulin-like growth factor receptors: use of semisynthetic insulin analog probes.

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)

Gonadotropin releasing hormone agonist (nafarelin) test to differentiate gonadotropin deficiency from constitutionally delayed puberty in teen-age boys--a clinical research center study.

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.

The prolactin response to thyrotropin-releasing hormone does not distinguish teenaged males with hypogonadotropic hypogonadism from those with constitutional delay of growth and development.

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.

Growth hormone therapy of Turner syndrome: the impact of age of estrogen replacement on final height. Genentech, Inc., Collaborative Study Group.

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.

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.

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.

Quantitation of urinary somatomedin-C and growth hormone in preterm and fullterm infants and normal children.

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.

Maturation of gonadotropin and sex steroid responses to gonadotropin-releasing hormone agonist in males.

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.

Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women.

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.

Growth hormone in adolescence. Normal and abnormal.

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.

Dysregulation of cytochrome P450c 17 alpha as the cause of polycystic ovarian syndrome.

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.

Growth hormone for short stature not due to classic growth hormone deficiency.

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.

Use of nafarelin for testing pituitary-ovarian function.

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

Insulin-like growth factors, insulin-like growth factor binding proteins and ovarian androgen production.

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.

Somatomedin-C/insulin-like growth factor-I as a modulator of growth during childhood and adolescence.

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.

Importance of receptor occupancy, concentration differences, and ligand exchange in the insulin-like growth factor I receptor system.

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.

A longitudinal study of the relationship of plasma somatomedin-C concentration to the pubertal growth spurt.

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.

Height prognosis of children with true precocious puberty and growth hormone deficiency: effect of combination therapy with gonadotropin releasing hormone agonist and growth hormone.

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.