Massive extranglandular aromatization of plasma androstenedione resulting in feminization of a prepubertal boy.

This report describes the mechanism of origin and the quantity of estrogen produced in a prepubertal boy who developed severe feminization at 8 yr of age as the result of a heretofore undescribed metabolic abnormality. The clinical findings were gynecomastia and accelerated linear growth and bone maturation. At the time feminization developed, there were no signs of growth or development of the otherwise normal prepubertal male external genitalia or any increase of muscle mass that normally accompanies male puberty. The hyperestrogenism was found to be the consequence of massive extraglandular conversion of plasma androstenedione to estrone. During a 6-mo period of study, the plasma production rate of androstenedione ranged from 1.2 to 1.6 mg/day. More than 55% of plasma androstenedione was metabolized by aromatization to estrone which, in turn, was extensively sulfurylated in the tissue sites of aromatization before its entry into the blood. Thus, estrone sulfate was the final product in the aromatizing sites, and the plasma production rate of estrone sulfate derived from plasma androstenedione was 782 mug/24 h. The extent of extraglandular conversion of plasma androstenedione to estrone measured in this boy was 50 times that observed in two normal prepubertal boys. Moreover, 94% of the extraglandular aromatization occurred in extrahepatic sites. The metabolic clearance rate of plasma androstenedione, 2,380 liters/day per m(2), was markedly increased in this boy. Approximately 1,500 liters of plasma androstenedione clearance was accounted for by extrahepatic, extraglandular aromatization. The fractional conversion of testosterone to estradiol, 0.16, was 50 times greater in this boy than that observed in normal young adult men. The total extent of aromatization of plasma prehormones was even greater in this boy inasmuch as evidence was obtained that aromatization of 16-hydroxysteroids, e.g. 16alpha-hydroxy androstenedione and 16alpha-hydroxy dehydroisoandrosterone (sulfate), resulted in estriol formation independent of estrone formation. Thus, extensive extrahepatic, extraglandular aromatization resulted in advanced feminization in this prepubertal boy by a previously undescribed metabolic abnormality.

Physiologic responses of juvenile-onset diabetic boys to muscular work.

The cardiorespiratory and metabolic responses of juvenile-onset diabetic (Dia) and nondiabetic (Con) boys to light, moderate, and maximal treadmill work were investigated. No significant differences were observed between the Dia and Con subjects in cardiorespiratory responses to maximal and submaximal work. The mean values for the Dia boys during maximal treadmill work for ventilatory volume, oxygen uptake, heart rate, and lactic acid were 91.5 L/min, 54.9 ml/kg . min, rate, and lactic acid were 91.5 L/nin, 54.9 ml/kg . min, 198 beats/min, and 7.0 mM/L, respectively. In the Dia boys, maximal-, light-, and moderate-intensity work produced significant plasma glucose decreases (P less than 0.05) of 1.64, 3.23, and 7.2 mM/L, respectively. In the Con boys, the submaximal work bouts were performed without significant change in plasma glucose levels, but glucose levels after maximal work were elevated 1.58 mM/L. Light and moderate work in both groups produced no changes in plasma triglycerides, free fatty acids, or lactic acid. However, for the Dia boys, maximal work was associated with a significant increase of 0.36 mM/L in triglycerides.

LH and melatonin secretion patterns in pubertal boys.

Four normal pubertal boys had plasma LH and melatonin measured at 20-minute intervals for 24-hours. All four subjects showed a significant augmentation of LH and melatonin during nocturnal sleep. There was also a significant correlation between the LH and melatonin levels (P less than 0.001). These data indicate that the peripheral concentrations of melatonin which occur during sleep are insufficient to prevent spontaneous LH secretion during puberty.

Luteinizing hormone and follicle-stimulating hormone secretory dynamics in Turner's syndrome.

In eight teenage patients with Turner's syndrome, LH and FSH were measured at 20-min intervals for 24 h. The 24-h mean LH and FSH levels ranged from 20.2-70.5 mIU/ml and 60.4-229 mIU/ml, respectively. There was a significant positive correlation between the individual LH and FSH levels in the eight patients; the common correlation coefficient was 0.449 (P less than 0.001). The 24-h mean estradiol level was measurable in only two of the patients and the 24-h mean testosterone level for the eight patients was 0.10 ng/ml. The mean LH concentration during sleep was significantly higher (P less than .01) than during waking. The mean FSH concentration during sleep was also significantly higher (P less than 0.05) than during waking. The LH and FSH peak levels after LRH were significantly correlated with the 24-h mean LH (r = 0.918; P less than 0.01) and FSH concentrations (r = 0.754; P less than 0.05), respectively.

Studies of gonadotropin-gonadal dynamics in patients with androgen insensitivity.

Four patients with androgen insensitivity had plasma LH and FSH measured at 20-min intervals for 24 h and at 15- to 30-min intervals for 3 h after the injection of LRH. Twenty-four-hour mean testosterone (T), estradiol, and androstenedione (delta 4) levels were also measured. Patients with androgen insensitivity had significantly elevated LH levels (P less than 0.05) and an increase in the number of LH secretory episodes (P less than 0.001) compared to normal subjects. The amplitude of the LH secretory episodes, expressed as the absolute increment, was significantly higher than normal controls (P less than 0.005). The LH response to LRH (absolute increment) was twice that of normal, but was not significantly different from normal subjects. The 24-h mean FSH levels were normal in three of the patients and elevated in one. This patient had the mildest degree of androgen insensitivity on clinical exam and the greatest degree of testicular atrophy. The 24-h mean T, estradiol, and delta 4 levels were higher than normal, but only the delta 4 was significantly increased (P less than 0.05). To determine if the elevated LH levels were in response to a decrease in the free T level, we measured T-binding capacity (TBG), TBG was higher than normal controls but was not significantly different, suggesting that elevated LH levels were probably in response to a decrease in T action at the hypothalamic-pituitary level. This was further supported by the inability of prolonged dihydrotestosterone administration to affect LH secretion in one of the patients with the Reifenstein syndrome.

Capillary basement membrane width in diabetic children.

The effect of juvenile onset diabetes mellitus on quadriceps muscle capillary basement membrane (QCBM) width has been examined by the electron microscopic morphometric method previously developed in this laboratory. The results demonstrate that in this age group QCBM thickening is strongly related to the age of the diabetic subject. As a result, in contrast to the almost constant thickening of QCBM that has consistently been documented in diabetic adults, QCBM hypertrophy is present in only 40 per cent of children with diabetes mellitus. As was previously shown to be the case in adults, in children, too, QCBM thickening is unrelated to the duration of the diabetes. Finally, the finding that QCBM hypertrophy is present at the time of acute onset of juvenile diabetes mellitus in 30 per cent of children, coupled with the fact that this lesion is not affected by duration of hyperglycemia, strongly supports our previous conclusion that diabetic microangiopathy is independent of the hyperglycemia of this disease. On the other hand, barring the possibility that microangiopathy in the pancreas precedes that in muscle, these results represent evidence against the suggestion that basement membrane hypertrophy represents the primary lesion of the diabetic syndrome.

In vivo and in vitro studies on the effects of vitamin A on the chemiluminescent response of murine peritoneal exudate cells.

Retinoids are known to enhance macrophage function and enhance bacterial clearance during experimental infection. The purpose of these experiments was to determine if one indicator of macrophage activation, chemiluminescence (CL), was enhanced by retinoids. Peritoneal exudate cells (PEC) harvested from mice injected intraperitoneally for 5 days with retinol palmitate (25, 125, or 250 U/g body wt./d) showed significantly enhanced chemiluminescence (CL) when exposed to opsonized zymosan. A direct dose-response effect was observed, in that the more retinol palmitate was injected, the more CL was observed. The same dose of retinol palmitate injected subcutaneously did not result in enhanced CL. In vitro incubation of murine PEC with physiological concentrations of retinol palmitate or retinoic acid for 1, 6 or 24 h did not result in enhanced CL. The reasons for the effect of the route of administration of retinol palmitate are unknown, but may include poor absorption from the site of subcutaneous injection or an adjuvant effect when injected intraperitoneally due to the particulate nature of the water-dispersible retinol palmitate preparation.

Reliability and validity of the Diabetes Family Behavior Scale (DFBS).

The Diabetes Family Behavior Scale (DFBS) was designed to measure diabetes-specific family support. The purposes of this study were to refine the scale and to assess reliability and criterion validity in terms of relationship to metabolic control. The DFBS was administered to 321 children and adolescents with insulin-dependent diabetes mellitus (IDDM). Blood was drawn for determination of glycosylated hemoglobin (HbA1c). Based on an item-analysis procedure, the DFBS was revised to include 47 items with two subscales, one to reflect guidance-control and one to reflect warmth-caring. Acceptable internal consistency was found for the DFBS total score (.86), and for the guidance-control (.81) and warmth-caring (.79) subscales. There was a statistically significant relationship in the expected direction between DFBS total score and HbA1c (r = -.12, P < .03), and between the guidance-control subscale and HbA1c (r = -.17, P < .002).

A variation of vitamin D deficiency in children.

We report three children presenting with hypocalcemia, hyperphosphatemia, elevated levels of parathyroid hormone, low concentrations of 25(OH)-vitamin D, normal to elevated concentrations of 1,25(OH)2-vitamin D, and normal radiographs. Although these findings led to consideration of parathyroid hormone resistance, clinical and biochemical findings remained normal after discontinuation of therapy, suggesting a variation of vitamin D deficiency.

Low-dose continuous intravenous insulin infusion in childhood diabetic ketoacidosis.

We studied 58 children with diabetic ketoacidosis using a random, prospective protocol, with insulin administered either as a low-dose continuous infusion or as high-dose intermittent subcutaneous injections. There were no statistically significant differences between admission pH and glucose determinations or the time to metabolic correction. The incidence of hypoglycemia and hypokalemia was higher in patients receiving subcutaneous insulin. Insulin levels in the low-dose patients were 85--160 microU/ml. The insulin required to achieve metabolic recovery was 1.6 U/kg in the low-dose group and 4.5 U/kg in the high-dose group (p less than 0.01). Glucose administered at a rate of 3 to 4 g er unit of insulin infused in the low-dose group maintained a serum glucose of 150 to 250 mg/dl. Our studies suggest that low-dose intravenous insulin therapy is safe, as effective as high-dose intermittent subcutaneous injections and avoids the risks of hypoglycemia and hypokalemia. Meticulous attention to individual patient care, however, must remain the most important single variable.

Relative hyperglucagonemia in L-asparaginase-and prednisone-induced glucose intolerance in management of acute lymphocytic leukemia.

Ten children with acute lymphocytic leukemia developed transient diabetes mellitus during treatment with L-asparaginase and prednisone. Serum glucose, plasma insulin, and plasma glucagon levels were measured when the patients were hyperglycemic. Six of the children were restudied several months later when there were no clinical or laboratory signs of glucose intolerance. Hyperglycemia induced by L-asparaginase and prednisone was associated with depression of plasma insulin and, despite the inhibiting action of L-asparaginase on protein synthesis, a corresponding elevation of plasma glucagon. Thus patients with diabetes mellitus induced by L-asparaginase and prednisone have relative hyperglucagonemia similar to other patients with diabetes mellitus.