Arline L.A. Martin

Measles vaccine failures : lack of sustained measles-specific immunoglobulin G responses in revaccinated adolescents and young adults

The measles-specific antibody responses of seronegative adolescents and young adults were evaluated after revaccination. Of 1650 previously vaccinated healthy volunteers between the ages of 10 and 30 years, 4.4% were found to be seronegative for measles antibodies and 9.9% had equivocal titers. Seronegative volunteers were revaccinated to measles and followed serially for development of measles-specific IgG. Of 43 subjects followed for at least 1 year, only 58% developed and maintained positive antibody titers; 12% never developed positive titers and 30% initially developed titers that fell below positive levels within 1 year. The peak titers achieved by those subjects who responded transiently were lower than those achieved by subjects who developed sustained responses. Thus even after the recommended two dose schedule of the current measles vaccine, some adolescents and young adults lack protective titers of measles-specific antibody.

Constitutional Delayed Puberty in Males and Hypogonadotropic Hypogonadism: A Reliable and Cost Effective Approach to Differential Diagnosis

Forty-six male teenagers 13-19 years old with delayed puberty (DP) underwent gonadotropin releasing hormone (GnRH) and human chorionic gonadotropin (HCG) stimulation as part of their work-up. All were followed to age 18 and beyond. Thirty-seven had constitutional delayed puberty (CDP). Nine had hypogonadotropic hypogonadism (HH). At referral 34 youngsters with CDP were properly diagnosed when the lower limit for the luteinizing hormone (LH) response to GnRH (Factrel 0.1 mg i.v.) was set at 12 IU/l. Three boys with CDP failed to reach that level and were not assigned appropriately. All nine patients with HH had basal serum testosterone (T) < 50 ng/dl when first seen and LH responses to GnRH stimulation < 8.0 IU/l. In the late 1970s, five subjects with DP were given HCG 3,000 IU (two patients daily for 5 days; three on 3 alternate days). Serum T was measured before the first, and 48 hours after the last injection (day 7). With recognition of the long biological half-life of injected HCG and receptor downregulation by daily doses, the protocol was changed. In the early 1980s, the dose of HCG was randomized to either 500 IU or 1,000 IU given on 3 alternate days. T was measured before the first injection (basal), 48 hours later (day 3) and 48 hours after the third injection (day 7). At referral 35 patients with CDP, including one GnRH failure, met the criterion for a positive response to HCG stimulation based on their own reactions (T > 170 ng/dl on day 3; > 200 on day 7). Eleven patients with DP failed the test. Nine had HH and two had CDP. The nine patients with HH included the two given daily injections and the three given HCG 3,000 IU on 3 alternate days. Of the two with CDP, one, an obese boy with a normal GnRH test, only received 500 IU HCG (5.6 IU/kg), which may have been inadequate. The other failed both tests. Of the 35 responders, 17 (group 1) were given HCG 500 IU and 18 (group 2) were given 1,000 IU i.m. on 3 alternate days. Seven boys in group 1 and 12 in group 2 had serum T determined on day 3, and all 35 had T measured on day 7. There was no significant difference between the basal T levels in the two groups or in their responses to HCG, and the results were pooled. The combined data in the patients with CDP were then compared with those of the nine patients with HH, recognizing that the result on day 7 in the two patients given daily injections may reflect receptor down-regulation. Setting the limit for a normal T response at > 170 ng/dl 48 hours after a single injection of HCG and > 200 ng/dl after the third injection assigned all the patients with CDP appropriately. The data on the patients with HH are less complete, with only three T values 48 hours after the first injection However, even after three injections of HCG on alternate days, only one of nine patients with HH approached the lowest level achieved by the patients with CDP after a single injection. The data confirm that a basal serum T 50 ng/dl is evidence of the onset of puberty. In those with serum T < 50 ng/ dl our data suggest that a single injection of HCG 15 IU/kg, with serum T determined 48 hours later, is more discriminatory and offers the most reliable, easy to perform, least painful, and by far the most cost effective test to differentiate CDP from HH.

ENDOCRINOLOGY: Idiopathic hypoglycemia-a defect in hypothalamic ACTH-releasing factor secretion

Corticotropin releasing factor (CRF) deficiency has not previously been demonstrated as a cause of hypoglycemic convulsions. We have recently stuided 3 children who justify such a diagnosis. One child moreover has an identical twin who provided the ideal control in the various test situations. The presence of the a disorder in ACTH release was suggested by the absence of a response in plasma cortisol and plasma ACTH to insulin induced hypoglycemia as measured by radioimmunoassay, impaired prompt water diuresis, lack of elevation in urinary 17-OHCS following metyrapone administration despite adequate 11-B-hydroxylase inhinition and normal adrenocortial activation by exogenous ACTH. Normal insuline and growth hormone responses to glucose, arginine, tolbutamide and glucagon adminstration as well as catecholamine release by insulin induced hypoglycemia confirmed the isolated nature of the defect in keeping with the presence of a normal growth pattern and normal thyroid indices. That the defeat is one of hypothalamic activation of ACTH release rather than isolated ACTH deficiency was confirmed by the release of ACTH and rise in plasma cortisol following vasopressin administration. Two children had a history of low birth weight for gestation age. The third infant was born postmaute with respiratory distress. The available evidence suggests that this is an acquired defect rather than a genetically determined abnormality. Hypoglycemia due to a defect in hypothalamic activation of ACTH release may provide the explanation for fasting hypoglycemia and convulsions in children otherwise unexplained or masquerading as ketotic hypoglycemia.

The syndrome of congenital hereditary adrenal hypoplasia and hypogonadotropic hypogonadism.

Two brothers are reported with congenital hereditary adrenal hypoplasia and hypogonadotropic hypogonadism, who experienced difficulties in the neonatal period, with electrolyte disturbances suggestive of adrenal insufficiency in the younger sibling. They thrived nevertheless until age 5 to 6 years when they presented with unequivocal evidence of primary adrenocortical failure. Upon reaching the age of puberty spontaneous sexual maturation failed to occur despite normal gonadotropin levels. Lack of LH response to LHRH but normal elevation in plasma testosterone following HCG stimulation suggested GnRH deficiency. Ten other patients with congenital hereditary adrenal hypoplasia and pubertal failure reported in the literature are reviewed. All are males with histological confirmation of adrenal agenesis or hypoplasia in 7 siblings. Eight of the twelve patients presented with signs and symptoms of adrenocortical insufficiency in the neonatal period; three were treated temporarily and thrived without therapy for years before becoming symptomatic again. None of the patients experienced a normal puberty though five showed some elevation in plasma testosterone and two had gonadotropins in the pubertal range early on. Both the onset of adrenal failure and of gonadotropin deficiency are variable in this disorder. The presence of the syndrome in three half-brothers with the same mother but different fathers suggests X-linked inheritance. Although the exact nature of the genetic defect remains unknown, the association of congenital hereditary adrenal hypoplasia and hypogonadotropic hypogonadism is now sufficiently well documented to establish it as a recognizable inherited syndrome.

Simultaneous determination of cortisol and corticosterone in urine.

Abstract Urinary cortisol and corticosterone have been measured simultaneously without prior purification or chromatography using a fluorometric method which incorporates a correction for non-specific fluorescence. Non-corticoid fluorescence was corrected for by the introduction of a sample blank in which corticosteroid fluorescence has been altered by interaction with hydroxylamine. Daily excretion of cortisol in normal subjects from 18 to 120 μg with a mean of 51 ± 24 υg S.D. and of corticosteronre o to 16 μg with a mean of 3.0 ± 3.2 μg S.D. The demonstration of a circadian rhythm, low levels in patients with adrenocortical hypofunction, elevation in the third trimester of pregnancy and the expected responses to metyrapone and corticotropin illustrate the close correlation with adrenocortical activity.

Autonomous Hyperfunctioning Thyroid Nodules in Childhood and Adolescence.

Over the past five years the criteria for the diagnosis of an autonomous hyperfunctioning thyroid nodule were met by seven patients referred for evaluation of thyroid enlargement. There were 6 females and 1 male ranging in age from 4 to 19 years. Six of the patients were asymptomatic and clinically euthyroid with normal thyroid function studies. One patient had symptoms of thyrotoxicosis confirmed by elevated hormone levels and thyroidal radioactive iodine uptake. Serum T-3 elevated in 3 of the clinically euthyroid patients when first seen, showed variability on serial determinations suggesting that a single high level may not be diagnostic for T 3 toxicosis. Thyroid antibodies were absent from the sera of all patients. TRH stimulation showed a normal response in one and a blunted response in another patient. Sonography in 5 of the 6 euthyroid subjects proved valuable not only in determining the size of the nodule but also in demonstrating in addition the presence of smooth-walled cysts in all cases which appears to be a hallmark. One patient had the nodule ablated because of hyperthyroidism. Four others elected to have surgery for cosmetic reasons. Two patients with nodules less than 2.5 cm are being managed conservatively with careful observation of thyroid status and serial sonograms in view of the experience in adults that nodules less than 3.0 cm in diameter are less at risk of becoming toxic.

Preferential hepatic galactose uptake in the newborn

Previous studies demonstrated impaired carbohydrate tolerance with a delayed and excessive rise in plasma glucose and insulin following oral glucose in healthy full term newborns less than 24 hours of age. To evaluate the role of the liver in determining carbohydrate tolerance, galactose tolerance tests were carried out in 6 full term infants of comparable age. following a 3 hour fast, galactose (2 gr/kg) was given by gavage. Blood samples were obtained from umbilical vein and from heel sites before and half-hourly to 3 hours following galactose feeding. Results indicate a rapid rise in total sugar and glucose with an early peak following the galactose feeding with little change in insulin concentration in either umbilical or capillary blood. Paired data analysis revealed a significant difference between total sugar and glucose in umbilical venous blood which was absent in capillary blood. Similarly there was a significant difference between umbilical venous and capillary blood total sugar but no difference in glucose. The data indicate rapid hepatic uptake of galactose as opposed to glucose without change in circulating insulin. The concomitant rise in glucose suggests almost immediate conversion of galactose to glucose in the newborn, which is not seen in older children.