The nonhuman primate as a model of growth hormone physiology in the human being.

Our review confirms the close correlation of the physiology of GH secretion in the nonhuman primate and the human subject which has not been seen in any other animal model, at least from the studies available to date. Except for a discrepancy in the relationship of GH secretion during early sleep, there are no significant differences between the species that can not likely be explained by methodological differences. Even the discrepancy between nighttime GH secretion may be due to methods of studying the nonhuman subjects. But methodological problems are at the heart of the problem in primate research. Primates are expensive to buy ($800-$1200 is not unusual for an adult male), expensive to house ($2-$3 per day is customary), dangerous to work with (bodily injury and serious infections are equally worrisome to handlers), exquisitely sensitive to environmental factors (as noted above), and above all, the subject of appropriate concern from animal use committees: these factors easily explain the relative dearth of primate studies on GH physiology compared to rodent studies. Problems of handling the animals and ensuring their stable state are helped to large degree by facilities such as the Regional Primate Facilities in the United States. The studies reviewed above should clearly demonstrate that the primate model, in spite of all the difficulties involved, is invaluable in investigating physiological phenomenon impossible to pursue in the human being. But only studies offering fastidious attention to detail in this potentially unstable model of GH physiology are likely to answer more questions than they raise.

Hormone ontogeny in the ovine fetus and neonatal lamb. XX. Effect of age, breeding season, and twinning on the growth hormone (GH) response to GH-releasing factor: evidence for a homeostatic role of fetal GH.

The ovine GH (oGH) response to GRF (1-44 amide) was evaluated in 74 chronically catheterized fetal and neonatal lambs. After a 1-h control period, GRF was administered iv, and the oGH response was studied during the next 60 min. The following variables were analyzed: GRF dose, fetal or neonatal age, breeding season, and singleton or multiple pregnancy. One and 10 micrograms/kg GRF elicited a similar oGH response, which was greater (P less than 0.001) than the response to 0.1 microgram/kg GRF. GRF-stimulated oGH release was strikingly age dependent. The mean peak incremental oGH response in fetuses of 89-122 days gestation (294 +/- 55 ng/ml) was higher (P less than 0.05) than that in fetuses of 127-145 days gestation (136 +/- 19 ng/ml); the fetal response was much greater (P less than 0.005) than the mean peak increment in neonatal lambs (46 +/- 7 ng/ml). A remarkable difference in basal and GRF-induced oGH secretion was observed in both fetuses and lambs of ewes bred in the normal breeding season (on-season) and those bred out of season (off-season). In the neonatal lamb, the mean basal oGH concentration was higher (P less than 0.005) in the on-season (12 +/- 2 ng/ml) than in the off-season (7 +/- 0.5 ng/ml) neonatal lambs, as was the mean peak incremental oGH response to GRF (70 +/- 12 vs. 33 +/- 7 ng/ml; P less than 0.01). In contrast, in singleton, late gestational fetuses (127-145 days), the mean basal oGH concentration was lower (P less than 0.03) in the on-season (74 +/- 9 ng/ml) than in the off-season (124 +/- 18 ng/ml) fetuses, as was the mean peak incremental oGH response to GRF (136 +/- 9 vs. 292 +/- 41 ng/ml; P less than 0.005). Further, compared to the on-season, late gestational singletons, on-season twin fetuses had higher (P less than 0.0001) basal oGH levels (199 +/- 19 ng/ml) and peak incremental oGH responses (248 +/- 11 ng/ml). Moreover, off-season twin fetuses had the highest basal GH concentrations and the most striking increment in GH concentration after GRF treatment of any of the groups. The strikingly age-dependent pattern of the GRF-induced oGH response in fetal and neonatal lambs is compatible with the concept that the inhibitory influences or their effects on the somatotrope increase gradually during late gestation and sharply at birth.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunoreactive somatostatin and luteinizing hormone releasing hormone in median eminence synaptosomes of the rat: detection by immunohistochemistry and quantification by radioimmunoassay.

Somatostatin and LHRH were detected by radioimmunoassay in the synaptosome fraction obtained by homogenization and differential centrifugation of the rat median eminence. Both somatostatin and LHRH were demonstrated by electron microscopic immunocytochemistry in secretory granules within synaptosomes.

Hormone ontogeny in the ovine fetus. XVIII. The effect of an opioid antagonist on luteinizing hormone secretion.

Endogenous opioid-like peptides influence gonadotropin release in adult animals and man; however, the role of these peptides in the regulation of fetal LH secretion is not known. We administered naloxone hydrochloride (1.3 mg/kg iv), a specific opioid receptor antagonist, to 22 chronically catheterized ovine fetuses of gestational ages 94-143 days (term = 147 days). As a control, each fetus also received the vehicle on a separate occasion, the sequence of the studies being randomized. After the administration of naloxone, LH secretion increased from 38.6 +/- 5.8 to 114 +/- 21 ng/h ml-1 (P less than 0.001); LH release was not affected by administration of the vehicle. Morphine (13 mg/kg) and naloxone (1.3 mg/kg) were administered together to three fetuses (gestational age 94-105 days); LH secretion was sharply reduced from 411 +/- 14.3 ng/h ml-1 after naloxone alone to 53 +/- 17.5 ng/h ml-1 after the administration of both naloxone and morphine (P less than 0.01). The response to naloxone varied with gestational age. Fetuses of 94-115 days showed a significantly higher increment in LH secretion when given naloxone (112.3 +/- 30.7 ng/h ml-1) than did older fetuses of gestational age 126-143 days (64.8 +/- 20.8 ng/h ml-1) (P less than 0.02). These findings indicate that, in the ovine fetus endogenous opioid-like peptides exert a tonic suppressive effect on LH secretion at least as early as 94 days gestation. Moreover, the effectiveness of naloxone in augmenting LH release decreases with advancing gestational age. This latter observation supports the concept that, in the ovine fetus, endogenous opioid tone is not the sole factor involved in the dampened fetal LH secretion which is characteristic of late gestation.

Hormone ontogeny in the ovine fetus. XVI. Plasma immunoreactive somatomedin C/insulin-like growth factor I in the fetal and neonatal lamb and in the pregnant ewe.

The basic somatomedins [SMC/insulin-like growth factor I (IGF-I)] and the neutral somatomedins (multiplication-stimulating activity/IGF-II) exhibit different patterns during pregnancy and ontogeny. We have adapted a specific RIA for SMC/IGF-I to study the pattern of change of this growth factor in fetal, neonatal, and adult sheep plasma. Acid-ethanol extraction of the samples was performed to minimize the interference of the somatomedin-binding proteins in the RIA. Results are expressed in terms of a neonatal lamb reference plasma with an arbitrarily assigned potency of 1 U/ml (equivalent to 500 ng/ml purified human IGF-I). In chronically catheterized fetal and neonatal lambs, plasma SMC/IGF-I rose from 0.14 +/- 0.02 U/ml before 100 days of gestational age (term 147 days) to 0.22 +/- 0.01 U/ml between 101 and 144 days. In neonates (1-33 days), the mean plasma concentration of SMC/IGF-I was 0.93 +/- 0.07 U/ml. In adult sheep, plasma SMC/IGF-I was twice as high in rams as in nonpregnant ewes (0.88 +/- 0.06 vs. 0.44 +/- 0.03 U/ml); in pregnant ewes plasma SMC/IGF-I did not change significantly between the second and the last third of gestation and was always higher than the fetal levels. The rise in fetal plasma SMC/IGF-I around 100 days of gestation parallels the rise in fetal GH and PRL concentrations. The discrepancy between the present results and earlier reports based on bioassays and radioreceptor assays may be due to the presence of high circulating concentrations of IGF-II-like peptides in the ovine fetus. The striking sex difference in the plasma concentrations of SMC/IGF-I in adult sheep suggests that SMC/IGF-I generation or disposition is influenced by sex steroids.

Hormone ontogeny in the ovine fetus. XVII. Demonstration of pulsatile luteinizing hormone secretion by the fetal pituitary gland.

To determine whether pulsatile gonadotropin secretion occurs in the fetus, plasma immunoreactive ovine LH (oLH) concentrations were determined by homologous RIA in serial samples obtained in 51 chronically catheterized fetuses between 79 and 140 days gestation. Pulsatile secretion of LH was detected in 39 fetuses, with a peak amplitude ranging from 1.2-11.5 ng/ml (mean +/- SD, 4.5 +/- 2.3 ng/ml). The mean plasma oLH concentration between pulses was 0.4 +/- 0.23 ng/ml. The mean amplitudes of the LH pulses were similar in the age range studied, and a sex difference was not detected. The estimated interpulse interval (determined by dividing the total number of hours during which blood samples were obtained by the number of pulses demonstrated) was 2.4 h between 91 and 110 days gestation. The pattern of plasma oFSH concentration was examined in 20 fetuses between 98 and 123 days gestation. Six fetuses with gestational ages between 106 and 115 days had FSH pulses that were equal or more than 2 times the sensitivity of the RIA. This study demonstrates a pulsatile mode of LH secretion by the ovine fetal pituitary as early as 81 days gestation and provides indirect evidence for pulsatile LRF secretion by the fetal hypothalamus and an operative LRF pulse generator by midgestation, the earliest stage in gestation studied.

Interactions of a monoclonal antibody to the insulin receptor with receptors for insulin-like growth factors.

A monoclonal antibody to the human insulin receptor was tested for its ability to inhibit the binding of 125I-insulin-like growth factor I (IGF-I) and 125I-insulin-like growth factor II (IGF-II) to their receptors in human placenta membranes and cultured human IM-9 lymphocytes. In both placenta membranes and IM-9 cells, the antibody progressively inhibited the binding of 125I-IGF-I to its receptor with a potency that was 300-fold less than its ability to inhibit the binding of 125I-insulin to its own receptor. In contrast, in human placenta membranes, this antibody inhibited the binding of 125I-IGF-II to its receptor only slightly. These studies indicate, therefore, that this monoclonal antibody binds preferentially to the insulin receptor but also crossreacts to a lesser extent with the IGF-I receptor.

Predictors of early remission of hyperthyroidism in children.

Children with hyperthyroidism often require prolonged courses of antithyroid medication to achieve remission, and long-term compliance is problematic. To determine which clinical and laboratory features predict early remission, we reviewed the records of 191 patients less than 19 yr old with Graves' disease. We compared patients achieving remission within 2 yr (group 1, n = 27) with those who completed more than 2 yr of medical therapy but did not achieve a remission (group 2, n = 79). Patients who were in neither of the above categories (n = 85) were excluded from the statistical analysis. Variables that were measurable at the time of diagnosis, recorded in more than 50% of the study population and associated with early remission in the univariate analysis (P < or = 0.05), were entered into a stepwise multiple logistic regression analysis. Variables retaining a significant association with early remission (P < 0.05) were considered independent predictors of early remission. Patients achieving early remission were older (mean, 12.5 vs. 10.9 yr, P = 0.039) and had higher body mass indexes (BMI, 19.0 vs. 16.6, P = 0.002), higher BMI SD scores (-0.03 vs. -0.60, P = 0.004), lower heart rates (110 vs. 121, P = 0.023), smaller goiters (group 1: 60% with moderate/large goiter; group 2: 83%, P = 0.050), lower platelet counts (272 vs. 339 K/microL, P = 0.006), lower serum T4 and T3 concentrations at presentation (T4: 18.3 vs. 22.5 microg/dL, P = 0.015; T3: 439 vs. 613 ng/dL, P = 0.008), and were less likely to have a positive test for thyroid stimulating Igs (group 1: 50% vs. group 2: 93%, P = 0.008). Regression analysis identified BMI SD score and goiter size as independent predictors of early remission (P < 0.05). Eighty-six percent of patients with BMI SD score above -0.5 SD and minimal/small goiters achieved early remission, compared with 13% of those with BMI SD score below -0.5 SD and moderate/large goiters. We conclude that, of multiple clinical and laboratory variables associated with early remission, BMI SD score and goiter size are independent predictors. Algorithms employing these two variables can be used to facilitate counseling of patients and expedite therapeutic decisions.

Changes in basal and stimulated growth hormone secretion in the aging rhesus monkey: a comparison of chair restraint and tether and vest sampling.

We studied basal serum GH and GH responses to iv clonidine and insulin-induced hypoglycemia in a group of four young (5-7 yr old) and four older (10-14 yr old) adult male rhesus monkeys under two restraint conditions, chair adaptation and a tether and vest system, to determine what changes in GH secretion occur with aging. The serum GH response to iv administration of GH-releasing hormone (GHRH) was also studied in the groups under tether and vest restraint. Serum samples were collected every 15 min and assayed for GH using a human GH RIA and for cortisol using an enzyme-linked immunosorbant assay. GH and cortisol concentrations in the young and older groups were analyzed with analysis of variance (ANOVA). In the chaired studies the older animals had a lower mean 6-h basal GH concentration than did the younger animals (2.7 +/- 0.8 vs. 3.5 +/- 0.5 micrograms/L; P = 0.0002). Prestimulation GH was lower before clonidine and insulin in the older chaired group (1.1 +/- 0.5 and 2.3 +/- 0.6 micrograms/L, respectively) compared to the younger group (3.6 +/- 0.8 and 3.8 +/- 0.7 micrograms/L, respectively; P less than 0.001). Poststimulation GH was lower after clonidine and insulin in the older chaired group (3.2 +/- 2.4 and 7.1 +/- 2.8 micrograms/L, respectively) compared to the younger chaired group (6.3 +/- 2.2 and 10.3 +/- 3.0 micrograms/L, respectively; P less than 0.05), but the differences in GH increments were not statistically significant. In the tether and vest studies the older animals had a lower mean 6-h basal GH concentration than did the younger animals (1.7 +/- 0.4 vs. 3.5 +/- 1.2 micrograms/L; P less than 0.0001). Prestimulation GH concentrations were also lower in the older tethered animals before clonidine (2.1 +/- 0.3 micrograms/L) and GHRH (1.4 +/- 0.2 micrograms/L) compared to levels in the younger animals (3.1 +/- 0.9 and 3.2 +/- 0.7 micrograms/L; P = 0.0023 and P = 0.0001, respectively). The younger tethered animals had greater poststimulation responses to clonidine (8.7 +/- 3.0 micrograms/L), insulin (8.8 +/- 3.6 micrograms/L), and GHRH (6.0 +/- 2.4 micrograms/L) than the older animals (3.8 +/- 0.9, 3.9 +/- 2.5, and 2.9 +/- 0.7 micrograms/L; P less than 0.0001, P = 0.0025, and P less than 0.03, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Insulin-like growth factors (IGFs) and IGF-binding proteins in the developing rhesus monkey.

Rhesus monkeys follow a developmental pattern of serum insulin-like growth factor-I (IGF-I) levels similar to that found in humans. In these monkeys, serum IGF-I levels peak during puberty (2.5-4.5 yr of age in males). We have examined the developmental pattern of IGF-binding protein-1 (IGFBP-1), -2, and -3 in serum by Western ligand blotting, the levels of IGFBP-3, IGF-I, and IGF-II in serum by RIA, and the IGFBP mRNA levels of IGFBP-1, -2, and -3 in the livers of rhesus monkeys from fetal life through adulthood by Northern analysis. The pattern of the serum levels of the IGFBPs reflected the liver mRNA levels of the IGFBPs. The IGFBP-1 and IGFBP-2 liver mRNA and serum levels were highest in the fetus and first year of life and were very low after 4 yr of age. Conversely, the IGFBP-3 liver mRNA and serum levels were relatively low early in life and peaked during puberty. The serum levels of IGF-I and IGF-II were strongly correlated with the level of IGFBP-3. We conclude that the developmental pattern of IGFBPs in the rhesus monkey is similar to that in the human, and that serum IGFBP levels are probably regulated by the rate of IGFBP mRNA synthesis.

Endocrine, histological, and biochemical studies of adrenocorticotropin-producing islet cell carcinoma of the pancreas in childhood with characterization of proopiomelanocortin.

Two 8-yr-old children, a boy and girl, are described with Cushing's syndrome secondary to ectopic ACTH-secreting pancreatic islet cell carcinomas. The girl, seen 28 yr ago, had strong presumptive evidence of ectopic ACTH production and hypercalcemia. The boy, studied recently, had strikingly elevated concentrations of plasma ACTH (1,500 pg/ml) and beta-lipotropin (beta LPH; 2,500 pg/ml) and showed no suppression of urinary 17-hydroxycorticoids or cortisol with low and high dose dexamethasone. He had increased plasma calcitonin (257 pg/ml), glucagon (442 pg/ml), lactate dehydrogenase (497 IU/liter), and alpha-fetoprotein (5,144 pg/ml). He also had hypokalemic alkalosis with elevated plasma deoxycorticosterone (70 ng/ml) and PRA (6.9 ng/ml.h) but normal plasma aldosterone (8.2 ng/dl) and 18-hydroxycorticosterone (7.6 ng/dl). Preoperative localization of the tumor was accomplished by computed tomographic scan of the abdomen with concurrent barium enema. Cell-free translation of the tumor mRNA produced authentic proopiomelanocortin of 35,000 mol wt, indicating that the ACTH and beta LPH were produced by the tumor from a common precursor. After removal of a large amount of metastatic tissue from the boy, clinical progression of the remaining tumor was monitored by measuring plasma ACTH and beta LPH. Episodic secretion of ACTH and beta LPH was demonstrated by taking frequent plasma samples while suppressing pituitary ACTH with oral dexamethasone. Chemotherapy and radiation proved ineffective in controlling the growth of his tumor.

Treatment of true precocious puberty with a potent luteinizing hormone-releasing factor agonist: effect on growth, sexual maturation, pelvic sonography, and the hypothalamic-pituitary-gonadal axis.

We used the LHRH agonist D-Trp6-Pro6-N-ethylamide LHRH (LHRH-A) to treat 19 children (12 girls and 7 boys) with true precocious puberty. Fourteen patients had idiopathic true precocious puberty, 4 had a hamartoma of the tuber cinereum, and 1 had a hypothalamic astrocytoma. Basal gonadotropin secretion and responses to native LHRH decreased within 1 week of initiation LHRH-A therapy, and sex steroid secretion decreased within 2 weeks to or within the prepubertal range. Ultrasonographic evaluation of the uterus indicated a postmenarchal size and shape in all 11 girls studied before treatment, which reverted to prepubertal size and configuration in 5 girls during LHRH-A therapy. The enlarged ovaries decreased in size and the multiple ovarian follicular cysts regressed. Sexual characteristics ceased advancing or reverted toward the prepubertal state in all patients receiving therapy for 6-36 months. All 5 girls with menarche before therapy had no further menses. Three girls had hot flashes after LHRH-A-induced reduction of the plasma estradiol concentration. Height velocity, SDs above the mean height velocity for age, and SDs above the mean height for age decreased during LHRH-A therapy; the velocity of skeletal maturation decreased after 12 months of LHRH-A therapy and was sustained during continued therapy over 18-36 months. In 4 patients, a subnormal growth rate (less than 4.5 cm/yr) occurred during LHRH-A therapy. Six patients had cutaneous reactions of LHRH-A, but no demonstrable circulating antibodies to LHRH-A. In 2 patients in whom LHRH-A therapy was discontinued because of skin reactions, precocious sexual maturation resumed at the previous rate for the ensuing 6-12 months; subsequently, they were desensitized to LHRH-A, and during a second course of therapy, their secondary sexual development and sex steroid levels again quickly decreased. LHRH-A proved an effective and safe treatment for true precocious puberty in boys as well as girls with central precocious puberty whether of the idiopathic type or secondary to a hamartoma of the tuber cinereum or a hypothalamic neoplasm.

Somatomedin-C in normal puberty and in true precocious puberty before and after treatment with a potent luteinizing hormone-releasing hormone agonist.

To explore further the relationship of gonadal sex steroids to the rise in somatomedin-C (Sm-C) during puberty, we studied a group of children with true precocious puberty before and after treatment which suppressed sex steroid output. Plasma estradiol and testosterone and serum acid-ethanol-extractable Sm-C were determined by specific RIAs in 7 boys and 12 girls with true precocious puberty before and at regular intervals during treatment with a potent LHRH-agonist (LHRH-A), D-Trp6-Pro9-NEt-LHRH. For comparison, Sm-C and sex steroid concentrations were determined in 266 normal adolescents and 37 normal prepubertal children, 1-9 yr of age. The mean +/- SEM Sm-C levels in normal male individuals peaked at 15 yr (2.46 +/- 0.23 U/ml) and at pubertal (genital) stage III (2.29 +/- 0.19 U/ml), and those in normal females reached their highest concentration at 12-15 yr of age and at pubertal (breast) stage III (2.47 +/- 0.15 U/ml). Sm-C concentrations correlated better with pubertal (genital or breast) stage than with chronological age for both sexes and better with testosterone levels in males than with estradiol levels in females. The mean +/- SEM Sm-C concentrations in both males and females with true precocious puberty were 2.07 +/- 0.16 U/ml before therapy and decreased significantly to 1.52 +/- 0.13 U/ml after 6 months of therapy. The mean Sm-C level of the patients remained significantly elevated for chronological age, but decreased into the normal range for bone age after 6-12 months of therapy. Sm-C correlated significantly with testosterone and estradiol levels, but not with growth rate. Mean nighttime GH secretion decreased significantly after 6 months of LHRH-A therapy. In summary, children with true precocious puberty have Sm-C elevations typical of normal puberty. The decrease in Sm-C levels after suppression of gonadal sex steroid output with LHRH-A is evidence that sex steroids are necessary to induce this elevation in Sm-C concentration. The decrease in GH secretion during LHRH-A therapy suggests that the effect of sex steroids on Sm-C levels during normal puberty is mediated, at least in part, through stimulation of GH secretion.

A role for epidermal growth factor in the morphological and functional maturation of the adrenal gland in the fetal rhesus monkey in vivo.

We determined the effects of epidermal growth factor (EGF) and beta-methasone on the growth and development of the adrenal gland of the fetal rhesus monkey in vivo between 121-128 days of gestation. The adrenal to body weight ratio was significantly greater (P < 0.05) in EGF-treated fetuses (0.988 +/- 0.046 x 10(-3) g/g) and significantly reduced (P < 0.05) in beta-methasone-treated fetuses (0.401 +/- 0.056 x 10(-3) g/g) compared with that in control fetuses (0.689 +/- 0.050 x 10(-3) g/g). The increase in adrenal weight with EGF administration was due to hypertrophy of definitive zone cells of the adrenal cortex, whereas the reduction in adrenal weight after beta-methasone treatment was due to a decrease in the size of definitive and fetal zone cells of the adrenal cortex. By Western analysis, EGF treatment induced a significant (P < 0.05) 2.8-fold increase in the amount of protein for 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta HSD) in the fetal adrenal. EGF also stimulated the induction of immunocytochemical staining for 3 beta HSD in transitional zone cells of the adrenal cortex. In contrast, beta-methasone resulted in 2.6-, 4.5-, and 6.6-fold significant decreases (P < 0.05) in the amount of protein for cytochrome P450 cholesterol side-chain cleavage, cytochrome P450 17 alpha-hydroxylase/17,20-lyase, and 3 beta HSD in the fetal adrenal. After beta-methasone treatment. 3 beta HSD staining was detected in some of the definitive zone cells, with no 3 beta HSD staining in the transitional zone. In conclusion, growth and functional differentiation of fetal primate adrenal gland can be accelerated prematurely by EGF and inhibited by glucocorticoid negative feedback.

Adolescent growth and maturation in zinc-deprived rhesus monkeys [see comment].

Growth retardation has been associated with zinc deficiency in adolescent human populations, but animal models were not available previously to explore this syndrome. Moderate dietary zinc deprivation (2 micrograms Zn/g diet) was introduced in female rhesus monkeys (Macaca mulatta; n = 10) from the beginning of puberty through menarche. Subgroups of animals (n = 4) continued to be fed the zinc-deficient diet through 45 mo of age (sexual maturity). Reduced weight gain and linear growth and lower plasma zinc concentrations (11.8 +/- 0.6 and 9.2 +/- 0.8 mumol/L in control and zinc-deficient monkeys, respectively) were evident during the premenarcheal growth spurt. Slower skeletal growth, maturation, and mineralization were recorded in the postmenarcheal period and some indicators of sexual maturation were delayed. Food intake was slightly higher in the zinc-deficient group than in controls. These data confirm that adolescent growth and maturation are vulnerable to disruption by moderate dietary zinc deprivation in nonhuman primates.

The therapy for hypothalamic-pituitary tumors.

Pituitary-hypothalamic tumors may profoundly affect endocrine functions. Although these are generally rare tumors of the central nervous system, they prominently figure into the differential diagnosis of children and adolescents with disorders of growth or puberty.

Puberty and its disorders in boys.

The secular trend toward an earlier age of puberty implicates health and nutrition as major determinants of the onset of sexual maturation. The pattern of hypothalamic stimulation of pituitary gonadotropin secretion causing gonadal steroid secretion that is active in the fetus, subdued in the child, and again awakened in the peripubertal period is well described, although the specific trigger of the initiation of puberty is unknown. Pubertal delay may have a cause in the CNS or in the gonad. Constitutional delay in pubertal development, a variant of normal, is difficult to differentiate from isolated gonadotropin deficiency, a permanent condition. However, a myriad of congenital defects, tumors, injuries, and infections can lead to hypogonadotropic hypogonadism, which may be diagnosed by associated physical findings. Gonadal abnormalities are characterized by elevated gonadotropin concentrations and often are associated with specific physical features. Early pubertal development may also be divided into etiologies based in the CNS or in other parts of the body. Idiopathic precocious puberty, in which the endocrine profile is identical to that of normal puberty, is seen in the early childhood period or as a minor variation from the normal range of the onset of pubertal development. Tumors of the CNS, however, are more often responsible for the youngest childhood cases of complete precocious puberty. Incomplete precocious puberty in boys can be caused by androgen production from the gonads or adrenal glands or can be caused by autonomous production of hCG. Variations of pubertal development are self-limited, although they may awaken parental or patient concerns. Thus, premature adrenarche is best differentiated from more serious and treatable causes of androgen production. Gynecomastia is usually treated with reassurance.

The treatment of precocious puberty.

Long-acting GnRH agonists are the treatment of choice for central precocious puberty. GnRH agonists are not effective in peripheral precocious puberty, but a number of other agents, including medroxyprogesterone acetate, ketoconazole, testolactone, and androgen antagonists, may be useful.

Transient neonatal 'athyreosis' resulting from thyrotropin-binding inhibitory immunoglobulins.

Recognition of transient forms of neonatal hypothyroidism is difficult because of the urgency of thyroxine treatment. In the present report the first child born to a mother with Graves' disease developed transient hyperthyroidism during the newborn period. The mother underwent radioactive iodine treatment and was maintained euthyroid on l-thyroxine. Two subsequent children were detected by newborn thyroid screen to have low thyroxine and markedly elevated serum thyrotropin (TSH) levels. Technetium 99 metastable and iodine 123 scans at 22 days of age showed the second child to be athyreotic. The third child was not scanned. All three children were nongoitrous at birth. Patients 2 and 3 had continuous TSH suppression with thyroxine therapy for 3 and 4 years. Thyroid function measurements after discontinuation of therapy for 8 weeks were normal, and both children had normal 123I thyroid scans. The mother was found to have potent TSH-binding inhibitory immunoglobulin (TBII) levels in her serum (85.5%). A fourth child with low thyroxine and elevated TSH was born to a mother on a regimen of l-thyroxine for hypothyroidism. 99mTc scan at 26 days of age showed no thyroid tissue and was normal at 3 months. TBII activity was 35% in the maternal serum and absent in the infant's serum. The above laboratory and clinical data are compatible with the blocking nature of TBII, resulting in transient newborn hypothyroidism and an athyreotic appearance on scan. The TBII measurement can be a useful predictor of neonatal hypothyroidism as well as confirm the transient nature of the disease in newborns.

Drug treatment in precocious puberty.

Precocious puberty, as defined by the onset of pubertal development before the age of 8 years in girls or 9 years in boys, can be classified into central and peripheral aetiologies. Central precocious puberty (CPP) results from early activation of the hypothalamic-pituitary-gonadal axis and has similar physical and hormonal characteristics to normal puberty. Extrapituitary gonadotrophin secretion or independent sex steroid secretion results in peripheral precocious puberty (PPP). Precocious puberty is characterised by rapid growth and advancement of skeletal age. The skeletal advancement is greater than the growth increase, so that final adult height is compromised. Long-acting gonadotrophin releasing hormone (GnRH) agonists are the current therapy of choice for central precocious puberty, having demonstrated effectiveness in halting the precocious development associated with this condition with minimal side effects. GnRH agonists are not effective as therapy for peripheral precocious puberty, but a number of other agents have been used with some success. These include androgen antagonists, testolactone, ketoconazole, and medroxyprogesterone acetate. The use of GnRH agonists has been associated with an increase in predictions of final height; however, continuing studies in treated cohorts are necessary to determine the true benefit of any of these agents on increasing ultimate height.