Growth hormone isoforms in a girl with gigantism.

Several previous investigations have suggested that there may be different growth hormone isoforms in patients with acromegaly. We used three different site-specific monoclonal antibodies (MAbs) to investigate growth hormone (GH) isoforms in serum from an 8 year-old girl with a GH and prolactin secreting adenoma. The pattern of GH-immunoreactivity was dependent on the circumstances of collection. Serum obtained after oral glucose had very little cross reactivity with MAb 352 although concentrations of up to 15 micrograms/l were found with two other MAbs, 033 and 665. MAb 352 does not recognize the 20,000 dalton isoform of GH (20K) while both MAb 033 and 665 do. The same pattern of GH immunoreactivity (low MAb 352, equal and higher MAb 033 and 665) was seen in other baseline samples. In contrast, samples obtained after TRH/GnRH showed immunoreactivity patterns expected for a mixture of 22,000 dalton isoform of GH (22K) with only a small amount of 20K. GH samples obtained during sleep showed both patterns with episodic peaks with equal immunoreactivity superimposed on the basal pattern (decreased activity with MAb 352). Affinity chromatography of basal samples showed that a portion of the GH immunoreactivity was neither 22K nor 20K, although in stimulated samples, over 70% of GH was 22K or 20K GH. In conclusion, the nature of GH isoforms present in serum varies with GH concentration. These differences may contribute to the known difficulty in correlating disease activity and random GH measurements in patients with GH secreting adenomas.

Carbohydrate absorption from one serving of fruit juice in young children: age and carbohydrate composition effects.

OBJECTIVES: To test the hypotheses that: the efficiency of carbohydrate absorption in childhood increases with age, and decreased carbohydrate absorption occurs more frequently with juices containing more fructose than glucose and/or sorbitol than with juices which contain equal amounts of fructose and glucose and are sorbitol-free. METHODS: One hundred and four healthy children were recruited from the Ambulatory Center at Maimonides Children's Center. They were assigned to one of three age groups: approximately 1, 3 and 5 years of age. Each child received one age-specific dose (by randomization) of one of four juices: a) pear juice which contains fructose in excess to glucose and a large amount of sorbitol; b) apple juice which is similar to pear juice in its fructose to glucose ratio but contains four times less sorbitol than pear juice; c) white grape juice or d) purple grape juice both of which contain equal amounts of fructose and glucose and are sorbitol-free. Breath hydrogen excretion (BH2) was utilized as the index of carbohydrate absorption. It was measured in fasting children and at 30-minute intervals for 3 hours after drinking the single serving of juice. Multiple breath hydrogen related parameters were quantified and results were expressed as: BH2 peak, area under the curve, and degree of carbohydrate malabsorption. After the test, parents completed a questionnaire and recorded signs and symptoms of intestinal malabsorption for 24 hours. RESULTS: Pear juice related BH2 levels were significantly higher among children 1 and 3 years of age as compared to the levels achieved after the other juices. Apple juice related BH2 levels were significantly higher only among the youngest age group of children. There was no significant difference in carbohydrate absorption among the 5 year old children regardless of the juice consumed. Incomplete carbohydrate absorption (BH2 peak above 20 ppm) occurred more frequently after pear juice consumption (84%) than after apple juice (41%) or grape juice (white 20%, purple 24%) [p < 0.05]. Further outcome measures of BH2 excretion did not elicit differences beyond those detected by the above-mentioned parameters. Parents reported diarrhea in six children after pear juice, two after apple juice and two after purple grape juice and these children had the highest BH2 levels in their respective groups. No other symptoms were reported. CONCLUSIONS: The data show that the efficiency of carbohydrate absorption of one age-specific serving of juice increases with advancing age of children. Decreased carbohydrate absorption occurs more often after ingestion of juices that contain more sorbitol, a nonabsorbable sugar and higher concentrations of fructose over glucose than after ingestion of juices which lack sorbitol and contain equal amounts of fructose and glucose.

Evaluation of differential effects of carbohydrate and fat intake on weight gain, serum IGF-1 and erythrocyte Na+K+ATPase activity in suboptimal nutrition in rats.

OBJECTIVE: Suboptimal nutrition leads to growth delay, frequently without over clinical or biochemical signs. We hypothesize that changes in serum IFG-1 and erythrocyte sodium-potassium ATPase activity (ENKA) may be indices of suboptimal nutrition. METHODS: Male Sprague-Dawley rats were pair-fed for 4 weeks with balanced diets of different carbohydrate (CHO) to fat (FAT) ratios (3:1, 2:1, and 1:1) and three levels of energy intake (ad-libitum, 80%, and 60%), corrected for actual body weight). Daily weight gain and weekly tail growth were monitored while ENKA, serum total protein, T3, insulin and IGF-1 were measured after four weeks. Refeeding experiments were also performed with the 3:1 and 1:1 CHO:FAT diets, including 4 weeks of dietary restriction and one week of ad-libitum feeding. RESULTS: Weight gain, tail growth, and IGF-1 decreased (p < 0.05) in all groups after 1 week of dietary restriction. A decrease in ENKA (p < 0.05) was found in rats that consumed 60% of ad-libitum energy intake only after 4 weeks. At the end of dietary treatment, weight gain was higher (p < 0.05) in rats fed the 3:1 CHO:FAT diet. In contrast, when energy was restricted to 80% or 60% of ad-libitum intake, rats fed the 1:1 CHO:FAT diet gained more weight (p < 0.05) compared to the 3:1 and 2:1 CHO:FAT diets. After 1 week of refeeding body weight, tail growth and ENKA returned to control values while serum IGF-1 levels remained depressed. CONCLUSIONS: Acute nutritional changes are clearly detected by a reduction of serum IGF-1 while ENKA may be a useful index for assessing chronic suboptimal nutrition.

Testing cord blood human chorionic gonadotropin as a surrogate marker for early identification of human immunodeficiency virus-1 infection in children.

We measured human chorionic gonadotropin (hCG) in cord sera of 22 infants born to women infected with the human immunodeficiency virus-1 (HIV-1). hCG was also determined in cord sera from 173 infants born at a suburban hospital to HIV-1-seronegative women. The findings indicate that 16 (9%) of 173 HIV-1-seronegative samples had hCG levels greater than 90 IU/L (values were distributed as a Poisson curve). In contrast, 8 (36%) of the 22 infants born to HIV-1-infected women had hCG levels in excess of 90 IU/L, and 7 (88%) of these were shown to be HIV-infected. The remaining 14 infants born to HIV-1-infected women had low hCG levels, and 3 (21%) of the 14 had HIV infection. Mean follow-up time for HIV-uninfected infants was 17.5 months (range 9 months to 3 years). A statistically significant association between maternal-fetal HIV-1 transmission and hCG levels > or = 90 IU/L in cord sera was observed (p = 0.02). The difference between CD4 counts among mothers who transmitted HIV and those who did not was also statistically significant (p = 0.025). On the basis of this study's findings, we propose that cord blood hCG may serve as a surrogate marker for HIV-1 infection. Testing hCG levels in cord sera is an inexpensive and readily available screening test for early identification of infants at increased risk for getting HIV-1 from their mothers.

Carbohydrate absorption from fruit juice in young children.

OBJECTIVE: To compare carbohydrate absorption following ingestion of apple juice and white grape juice in 28 healthy children. DESIGN: Randomized, double-blind crossover study. SETTING: Outpatient pediatric clinic at Maimonides Medical Center. PARTICIPANTS: A total of 18 healthy infants (mean age 6.3 months) and 10 toddlers (mean age 18.0 months), representing those ages when juice is first introduced (6 months) and when juice comprises a large portion of the diet (18 months). METHODS: Breath hydrogen (H2) testing was performed after age-specific servings of white grape juice or apple juice, 4 and 8 ounces respectively, were consumed. These portions provided approximately 1 g of fructose per kg of body weight. Breath H2 responses of > 20 ppm were considered positive, indicating incomplete absorption of fruit juice carbohydrates. RESULTS: In the combined age groups, carbohydrate malabsorption occurred more frequently after apple juice consumption (54%) than after white grape juice (19%; P < .001). Significant differences in area under the breath H2 curve (AUC) were also found between the two juices in both age groups. Among toddlers, the differences between the mean peak breath H2 responses were significant (48 ppm after apple juice consumption compared with 12 ppm after white grape juice; P < .001). These differences were not significant in the infant group. Significant differences (P < .05) were seen between the two age groups after consumption of apple juice; the toddlers exhibited a greater number of positive breath H2 responses and higher peak responses compared with the infants. Data from the children who drank both juices showed significant differences in peak breath H2 responses after consumption of apple juice compared with white grape juice (P < .005). CONCLUSIONS: The study demonstrated less carbohydrate malabsorption following ingestion of white grape juice compared with apple juice in healthy 6- and 18-month-old children.

Disturbances in growth hormone secretion and action in adolescents with anorexia nervosa.

Women in whom anorexia nervosa develops during adolescence have failure of linear growth associated with low levels of insulin-like growth factor I (IGF-1). To investigate the pathophysiology of growth retardation in adolescents with anorexia nervosa, we measured basal growth hormone (GH), growth hormone-binding protein (GHBP), IGF-1, and insulin-like growth factor binding protein-3 (IGFBP-3) in three groups of patients: (1) 28 recently hospitalized female adolescents with anorexia nervosa, (2) 23 of the same patients after partial weight restoration, and (3) 28 healthy control subjects matched for age, sex, and pubertal stage. Fasting GH levels in group 1 did not differ significantly from those in group 3. In contrast, serum GHBP (p < 0.001), IGF-1 (p < 0.001), and IGFBP-3 (p < 0.01) were significantly lower in group 1 than in group 3. Serum GHBP and IGFBP-3 levels were positively correlated with body mass index. Serum GHBP levels were low in patients in all five pubertal stages and even in those shown to have adequate GH secretion. In group 2 (after refeeding) the serum IGF-1 concentration increased significantly and GHBP and IGFBP-3 returned to normal. We conclude that patients with anorexia nervosa have diminished GH action resulting in decreased secretion of IGF-1. The positive correlation with body mass index and the reversibility with refeeding suggest that these changes are secondary to malnutrition. Altered GH function that occurs during the years of active growth can explain the growth retardation seen in anorexia nervosa.

Thyroid function in children with perinatally acquired antibodies to human immunodeficiency virus.

We measured T4, T3, TSH, and TBG in 53 children (both asymptomatic and symptomatic) with human immunodeficiency virus (HIV) antibodies, and 17 controls. Although most had normal T3 and T4 levels, two children with acquired immuno-deficiency syndrome (AIDS), who were very ill when studied, had low T3 values. TBG and TSH levels were higher in children with AIDS than in other HIV-infected children or controls (P < 0.005). Increased TSH levels were found in 5 children with AIDS who were recovering from severe illnesses. TSH levels returned to normal without treatment. In summary: 1) the pattern of thyroid abnormalities in children with AIDS was different from that seen in healthy controls, critically ill children, other HIV-infected children, and HIV-infected adults; 2) if an increased TSH is found, measurement should be repeated before instituting thyroxine therapy; 3) an increased TBG is not seen in HIV-infected children until clinically evident AIDS is present.

Circulating growth hormone isoforms in girls with Turner's syndrome.

To evaluate the presence of different GH isoforms in serum of girls with Turner's syndrome, we measured the serum GH content using RIAs with three different site-specific monoclonal antibodies (MAbs). We compared the results to those obtained with authentic GH and GH isoforms. Compared to pituitary GH (mol wt, 22K daltons) as the standard for all three MAbs, serum from girls with Turner's syndrome did not displace tracer [125I]GH equally with all three MAbs. The relative amounts of GH-immunoreactive material found in Turner's syndrome were different from the amounts observed in normal adults and most children with idiopathic short stature. The presence of GH, other than 22K GH, in serum from girls with Turner's syndrome was confirmed by affinity chromatography. The existence of different isoforms of GH, as shown by different cross-reactivity patterns with different MAbs to GH, may explain the conflicting results reported for GH secretion in girls with Turner's syndrome.

L-arginine decreases the infiltration of the kidney by macrophages in obstructive nephropathy and puromycin-induced nephrosis.

We examined the effect of 1% L-arginine in the drinking water on the infiltration of the kidney by macrophages in rats with puromycin aminonucleoside-induced nephrosis (PAN) and in rats with bilateral ureteral obstruction (BUO) of 24 hours duration. Rats given L-arginine in the drinking water for three days before BUO or PAN was initiated had a greater glomerular filtration rate after release of BUO or induction of PAN than similar rats not given L-arginine (P < 0.0001). Administration of L-arginine decreased the renal infiltration by macrophages in rats with PAN (P < 0.0001) or BUO (P < 0.0001) compared to rats with PAN or BUO given tap water alone. Chemotaxis studies suggested that macrophages were activated during obstruction as evidenced by the greater random migration of peritoneal macrophages obtained from rats with 24-hour urethral obstruction than from sham-operated rats (SOR; P < 0.0001). In vitro, maximal chemotaxis induced by 7% zymosan-activated serum (ZAS) in peritoneal macrophages from SOR was enhanced by low (10(-6) to 10(-5) M) and decreased by high concentrations (10(-3) to 10(-2) M) of L-arginine in the incubation medium. Migration of macrophages from rats with urethral obstruction was increased by 7% ZAS but the increase diminished with high concentrations of L-arginine (10(-3) to 10(-2) M). Random migration of peritoneal macrophages obtained from rats with urethral obstruction given L-arginine prior to obstruction was significantly lower than that of peritoneal macrophages obtained from similar rats given tap water alone prior to obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadotropin-associated psychosis in perimenstrual behavior disorder.

Sexually provocative and violent behavior have been reported as a result of excess androgens. We now report a temporal relationship between increased gonadotropin levels and behavioral changes in two adolescent girls who presented with a history of aggressive and bizarre sexual behavior coincident with the onset of menarche. We evaluated the possibility of a cyclical hormonal cause with daily measurements of gonadotropins, androgens and estradiol levels and correlated the results with periodic reports on the girls' behavior. We concluded that a correlation exists between periods of extremely violent and sexually provocative behavior and peaks of gonadotropin hormone secretion, even though androgen levels were normal. Treatment with medroxyprogesterone acetate (Depo-Provera) in one case and with leuprolide acetate (Lupron-Depot) in the other suppressed gonadotropin levels, and behavior improved markedly. Thus, the behavioral changes (or psychosis) seen in these girls might have been induced by increased levels of gonadotropins.

Correlation between puberty and the development of autoimmunity to spermatozoa in men with cystic fibrosis.

OBJECTIVE: To test the hypothesis that puberty is a necessary factor in the pathogenesis of autoimmunity to sperm in men with cystic fibrosis (CF), we studied prepubertal and postpubertal males with CF versus an age-matched group of males with type 1 diabetes as controls. DESIGN: Sera from CF and diabetic males treated at University Hospital, State University of New York, Stony Brook, were tested by indirect immunobead binding for antisperm antibodies and by radioimmunoassay for testosterone (T), luteinizing hormone, and follicle-stimulating hormone. The finding of autoantibodies to spermatozoa was correlated with chronological age, as well as with clinical and hormonal pubertal status. RESULTS: Autoimmunity to sperm, as detected by humoral antisperm antibodies, was documented solely in postpubertal males, as judged by hormonal and clinical criteria. Eighty-three percent of sexually mature CF males and 6.3% (1 of 16) diabetic males exhibited autoantibodies to sperm. These antibodies were only detected when serum T levels were > 8.7 nmol/L (250 ng/dL). CONCLUSIONS: These results suggest that puberty, and presumably, active spermatogenesis is a requirement for the development of autoimmunity to sperm in men with CF.

Sustained improvement in growth velocity and recovery from suboptimal growth hormone (GH) secretion after treatment with human pituitary GH-releasing hormone-(1-44)-NH2.

The sustained effect of human pancreatic GH-releasing hormone [hpGHRH-(1-44)-NH2] on growth rate and GH secretory patterns was studied in 14 patients (10 males and 4 females; aged 10-16 yr; all Tanner stage I or II). Nine children had inadequate spontaneous GH secretion (ISGHS), while 5 had classic GH deficiency. Seven of 9 patients with ISGHS and 1 of 5 patients with GH deficiency were given 2 sc injections/day of 5 micrograms/kg GHRH for 2-3 months; the others received 5 pulses of GHRH (5 micrograms/kg BW.pulse) for 6 nights a week for 2-13 months, given every 3 h. Six of the nine ISGHS patients increased their growth velocity in response to GHRH therapy. These same six patients maintained an increased growth velocity for up to 24 months after GHRH was discontinued. The remaining three ISGHS patients did not show a significant growth response to GHRH administration. Neither a temporary nor a sustained growth response was correlated with spontaneous overnight GH secretion in these patients. In contrast, three of five classical GH deficiency patients exhibited increased growth velocity while undergoing GHRH therapy, but growth returned to preintervention rates upon discontinuation of treatment. The other two of the five classic GH deficiency patients failed to demonstrate any growth response to GHRH treatment. The increased growth velocity that was sustained for long intervals even after discontinuation of GHRH in ISGHS patients may indicate restoration of normal regulation of the hypothalamic-pituitary GH secretion axis.

The role of adrenocorticotropin testing in evaluating girls with premature adrenarche and hirsutism/oligomenorrhea.

To identify biochemical predictors for future development of hirsutism and/or oligomenorrhea (H/O) in girls with premature adrenarche (PA), we performed dexamethasone-suppressed ACTH stimulation tests in girls with PA (n = 46), young women (n = 44) with H/O, and adult women (n = 31). Cortisol, androstenedione, dehydroepiandrosterone, and 17-hydroxyprogesterone were measured. Seven girls with PA (15%) and seven with H/O (16%) had evidence of nonclassical adrenal steroid biosynthetic defects [nonclassical congenital adrenal hyperplasia (NCAH)]. Twenty-five girls with PA (54%) and 28 girls with H/O (64%) had the moderately elevated 17-hydroxyprogesterone response to ACTH that has been reported in obligate heterozygotes for 21-hydroxylase deficiency. There were no clinical features that distinguished the girls with NCAH from the others. ACTH testing is an important tool in distinguishing those girls with PA and H/O who have NCAH. Although we could find no differences in other adrenal steroid hormones that might predict which of the other girls with PA might late develop H/O, black girls comprised a substantially smaller fraction of the population with H/O than of the population with PA (2% vs. 26%; chi 2 = 8.5; P less than 0.005). This observation suggests that PA, in blacks who do not have NCAH, is more likely to be a benign condition/than in other ethnic groups.

Subdiaphragmatic vagotomy in rats induces systemic hypertension and sodium retention.

We examined the acute effects of bilateral subdiaphragmatic vagotomy (BSV) on blood pressure and renal function in female Sprague-Dawley rats. Mean arterial pressure was greater (p < 0.0001) in rats with BSV than in sham-operated rats (SOR). Rats with BSV had a significantly lower effective renal plasma flow (p < 0.01), total sodium excretion (p < 0.005), fractional sodium excretion (p < 0.01), urine flow (p < 0.01), and fractional excretion of water (p < 0.02) than SOR. The glomerular filtration rate was not significantly different between the 2 groups of rats. Plasma potassium was greater in rats with BSV than in SOR (p < 0.02). Pretreatment with an inhibitor of the angiotensin-converting enzyme prevented the above changes in rats with BSV. Changes in renal function and mean arterial pressure could not be attributed to antidiuretic hormone since plasma levels of antidiuretic hormone were lower in rats with BSV than in SOR (p < 0.002). In addition, the activity of the sympathetic system was decreased in rats with BSV, as suggested by the lower plasma levels of epinephrine (p < 0.003) and norepinephrine (p < 0.02) and the significantly lower renal tissue concentrations of norepinephrine (p < 0.03). No significant changes in renal tissue concentrations of acetylcholine or choline, its precursor, were observed in BSV rats when compared to SOR, suggesting a lack of renal parasympathetic innervation. Plasma renin activity was lower in rats with BSV (p < 0.02) than in SOR, but this effect was blunted in rats given an angiotensin-converting enzyme inhibitor prior to BSV.(ABSTRACT TRUNCATED AT 250 WORDS)

Blunted growth hormone responses to clonidine in adolescent girls with early anorexia nervosa. Evidence for an early hypothalamic defect.

We studied growth hormone (GH) levels in 14 adolescents with anorexia nervosa (AN), 12-20 years of age. All had amenorrhea and the duration of symptoms ranged from 2-24 months. There was no difference in unstimulated GH between the girls with AN and endocrinologically normal girls. However, the GH response to the alpha-adrenergic agent clonidine was blunted (less than 10 ng/ml) in 11 of 14 girls with AN. Our results of a normal basal GH level and blunted response to stimulation is in contrast to some reports of high basal GH levels and an exaggerated response to pituitary stimulation although it agrees with other studies. Our patient population was younger and at an earlier stage of the disease (12 with symptoms for less than 1 year) than the AN patients previously reported to have elevated GH secretion. In view of studies that report an elevated GH response to growth hormone releasing factor, our results suggest that the AN patient's abnormalities in GH secretion may result from an abnormal hypothalamic response to adrenergic stimuli. This hypothalamic abnormality might also contribute to the growth failure seen in adolescent girls with AN.

Characterization of digoxin-like materials in human cord serum.

Human cord serum contains substantial amounts of materials that cross-react in radioimmunoassays for digoxin. The average content of digoxin-like immunoreactivity in mixed cord serum is 0.3 +/- 0.05 ngE/ml compared to less than 0.05 ngE/ml in serum from normal adults. After solvent extraction, the major digoxin-like materials present in cord serum coelute on Sephadex LH-20 column with the steroid sulfate fraction. The steroid sulfates are digoxin-like materials because they cross-react in the digoxin RIA. If the amount of dehydroepiandrosterone sulfate, 16 alpha-hydroxydehydroepiandrosterone sulfate, and 15 beta-hydroxydehydroepiandrosterone sulfate present in cord serum and the amount of digoxin-like material present in the same serum are considered, then up to 90% of the digoxin-like materials present can be accounted for on the basis of the steroid sulfates present. However, although steroid sulfates contribute to the digoxin immunoreactivity in both serum and breast cyst fluid, digoxin-like materials are present in breast cyst fluid that are not present in cord serum.

Digoxinlike materials in human breast cyst fluids.

Digoxinlike materials (DLMs) are compounds found in animals that (1) cross-react with digoxin antibodies in specific radioimmunoassay procedures and (2) bind to Na+, K(+)-ATPase and inhibit its activity. DLMs may play a part in the regulation of electrolyte composition. We have determined DLM concentrations in breast cyst fluids and found that these fluids were a rich source of DLMs. Total DLMs were elevated in fluids with type 1 electrolyte composition (high K+ and low Na+ content) when compared to fluids with type 2 composition (low K+ and high Na+ content). Chromatographic studies showed that the basis for the increase was the presence of an additional DLM in the type 1 cyst fluids rather than an increased concentration of the same DLM present in both types of fluids. We propose that this additional DLM may have a role in the accumulation of K+ ions in type 1 fluids. In addition, 7 of 80 cyst fluid samples subjected to high-performance liquid chromatography had a large UV-absorbing peak at 6.4 minutes. Four of these samples were taken from women who later developed breast cancer; information on the subsequent medical history of the other 3 women was unavailable. We suggest that the presence of this material in cyst fluid may be a marker of risk for development of breast cancer.

Dehydroepiandrosterone sulfate levels are not suppressible by glucocorticoids before adrenarche.

We measured dehydroepiandrosterone sulfate (DHEA-S) levels in children before and after high dose prednisone therapy. In older children (postadrenarchal), there was a 70% decrease in DHEA-S levels after 1 week. However, even after a month of therapy, DHEA-S was detectable in serum. In contrast, in younger (preadrenarchal) children, the low initial DHEA-S levels were not decreased by prednisone therapy. These findings suggest that there are two distinct regulatory pathways leading to DHEA-S, one of which is independent of ACTH.