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Biomedical subjects

J F Crigler

Publications and source records attributed to J F Crigler.

At least 37 records · Page 2Linked to original sources
PubMed1986

Thyrotropin-receptor autoantibodies in children and young adults with Graves' disease.

Thyrotropin (TSH)-receptor autoantibodies were assessed by measurement of 125I-bTSH binding inhibition in 32 patients with juvenile-onset Graves' disease (one of whom was studied twice) and 16 normal control subjects. Thirteen (76.5%) of 17 thyrotoxic patients had significantly elevated TSH binding-inhibitory immunoglobulin (TBII) activity compared with eight (50%) of 16 patients who were in clinical remission and none of the control subjects. Mean TBII activity was significantly greater in thyrotoxic patients than in individuals in remission, except in one unusual patient in whom there was a discordance between TBII activity and in vitro thyroid-stimulatory activity. In eight euthyroid patients who were followed up for at least five months while not receiving treatment, assessment of TBII activity did not predict who would or would not suffer relapse at a later date. Thus, TBIIs are secreted in excess in juvenile Graves' disease, the titer decreasing as the disease remits. The TBII assay cannot be used as the sole predictor of when antithyroid medication can be withdrawn safely, however.

Adenylyl Cyclases↗
PubMed1986

Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls.

Spontaneous pubertal growth was studied in eight patients with the syndrome of androgen insensitivity to obtain information on the growth-promoting action of estrogens. In one additional patient (who had a gonadectomy before puberty), the effect of exogenous estrogens was studied. Mean age at peak height velocity (12.7 years) was closer to that in normal girls than to that in normal boys. Mean peak height velocity (7.4 cm/yr) was as in normal girls (7.3 cm/yr), but was lower than in normal boys (9.3 cm/yr). Bone age corresponded better to male standards. Mean adult height (172.3 cm) was lower than in normal men (-0.6 SD), but higher than in normal women (+1.4 SD). In the patient who had a gonadectomy, estrogen replacement caused a higher peak height velocity (12 cm/yr), but lower adult height (160.5 cm) than in the patients with intact gonads who received no treatments. We conclude that in normal girls, the pubertal growth spurt also results from the action of estrogens rather than of adrenal androgens. To ensure normal pubertal growth, physiologic estrogen replacement in hypogonadal females should be started at a bone age of about 11 years, and should not be delayed in the hope of achieving a greater mature height.

Adolescent↗
PubMed1986

Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche.

During puberty the effects of adrenal androgens upon skeletal maturation are obscured by the influence of gonadal steroids. Suppression of gonadarche with an analogue of luteinizing hormone releasing hormone (LHRHa) affords an opportunity to examine the onset and progression of adrenarche in the absence of pubertal levels of gonadal steroids in a controlled fashion and to explore the relationship between adrenal androgens and the rate of epiphyseal maturation. In 29 children with central precocious puberty, gonadarche was suppressed with LHRHa administration for 1-4 yr. During LHRHa exposure, dehydroepiandrosterone sulfate (DHAS) levels, as an index of adrenal maturation, were constant or increased in an age-expected manner. The change in bone age for change in chronologic age decreased from 1.7 +/- 0.1 to 0.49 +/- 0.05 (P = 0.00005), indicating that the LHRHa-induced return to a prepubertal gonadal steroid environment was associated with a slowing of skeletal maturation. DHAS levels were correlated with the rate of skeletal advancement before (r = 0.57, P = 0.001) and during 12 to 48 mo of exposure to LHRHa (r = 0.52, P = 0.003). A negative correlation of DHAS values with subsequent increases in predicted mature height was observed (r = -0.49, P = 0.007). Thus, in children with central precocious puberty, adrenarche progressed normally during LHRHa suppression of gonadarche. In children with the onset of progression of adrenarche during maintenance of a prepubertal gonadal steroid milieu, there was less evidence than in preadrenarchal children of a restraint upon skeletal maturation. These data suggest that adrenal androgens contribute importantly to epiphyseal advancement during childhood.

Adrenal Cortex↗
PubMed1986

Use of a potent, long acting agonist of gonadotropin-releasing hormone in the treatment of precocious puberty.

Studies utilizing the administration of GnRH in various GnRH-deficient models have revealed the critical importance of the dose and mode of delivery of this releasing factor in determining the subsequent pituitary response. Chronic administration of long acting GnRH agonists (GnRHa), like continuous infusion of high doses of the native peptide, results in suppression of pituitary gonadotropin secretion. This selective and reversible suppression of gonadotropin secretion suggested several therapeutic applications for these analogs, particularly in the treatment of central precocious puberty (CPP), a disorder for which the previously available therapies lacked uniform efficacy and were associated with potential side effects. In our series, 74 children with CPP have been treated during the last 5 yr with the potent GnRH agonist, [D-Trp6, Pro9-ethylamide(NEt)]GnRH. Having selected a dose and route of administration that produced uniform suppression of spontaneous and stimulated pituitary gonadotropin secretion, GnRHa therapy resulted in a fall of gonadal sex steroid levels into the prepubertal range, a halting or regression of secondary sexual development, and a complete cessation of menses. Growth velocity slowed during therapy, with this slowing more pronounced during prolonged treatment periods and among those patients with more advanced chronological and skeletal ages. Skeletal maturation was retarded to a greater degree than linear growth, with resultant increases in the predictions for adult stature. Moreover, these benefits have been achieved in the absence of significant side effects. Complete reversal of the suppression of gonadarche has followed discontinuation of therapy; however, patterns of growth and skeletal maturation after discontinuation of GnRHa administration remain to be characterized. Thus, the impact of GnRHa therapy on final height must await further longitudinal study. The selective nature of GnRHa suppression of gonadarche also permits an investigation of the natural history of adrenarche and its discrete influences upon skeletal growth and maturation. In addition, GnRHa therapy of CPP provides a unique opportunity to study the effects of gonadal sex steroids on GH secretion and somatomedin-C (Sm-C) generation during sexual maturation. Finally, the detailed characterization of children with precocious puberty has helped to define more precisely a subset of patients whose precocity occurs in the absence of demonstrable gonadotropin secretion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗
PubMed1985

Puberty without gonadotropins. A unique mechanism of sexual development.

Recent evidence suggests that a group of children exists in whom premature sexual maturation occurs in the absence of pubertal levels of gonadotropins; that is, they have gonadotropin-independent precocious puberty. We compared six boys and one girl with this disorder with four boys and five girls with central precocious puberty, in which there is a pubertal pattern of gonadotropin release. The two groups were similar in age of onset, degree of sexual development, growth velocity, and rate of skeletal maturation. A family history of precocity was noted in four of the boys with gonadotropin-independent precocity, and the girl had McCune-Albright syndrome. Children with central precocious puberty demonstrated a pulsatile release of gonadotropins, pubertal responses to luteinizing hormone-releasing hormone, and complete suppression of gonadarche after exposure to an analogue of luteinizing hormone-releasing hormone (LHRHa). In contrast, children with gonadotropin-independent precocity demonstrated an absence of gonadotropin pulsations, variable responses to luteinizing hormone-releasing hormone, lack of suppression of puberty in response to LHRHa, and cyclic steroidogenesis. Tissue from testicular biopsies performed in five of six boys with gonadotropin-independent precocity showed a range from incipient pubertal development of the tubules with proliferation of Leydig cells to the appearance of normal adult testes. We conclude that gonadotropin-independent precocious puberty is a distinct syndrome, of unknown cause, that may be familial and may have been responsible for many previously reported cases of precocious puberty.

Child↗
PubMed1984

Final height in estrogen-treated patients with Turner syndrome.

The growth effects of estrogen therapy in 37 adolescent girls with gonadal dysgenesis associated with various X chromosomal abnormalities were investigated. Nineteen patients (group 1) were treated at a mean of 14.3 years, and 18 patients (group 2) were treated at an average of 17.2 years. Final height was independent of the age estrogen therapy was initiated. Nevertheless, the growth responses to estrogens of groups 1 and 2 were different. For group 1, growth velocity significantly increased from 3.0 to 4.2 cm per year over the first year of therapy; for group 2, the corresponding velocities were not significantly different. Mean midparental height was significantly correlated with final height; however, karyotype, estrogen dosage, and duration of therapy were not significantly related to final height. The authors conclude that earlier estrogen therapy alone for patients with gonadal dysgenesis does not significantly compromise final height and produces development more in keeping with their normal adolescent peers.

Adolescent↗
PubMed1983

Long-term treatment of central precocious puberty with a long-acting analogue of luteinizing hormone-releasing hormone. Effects on somatic growth and skeletal maturation.

The gonadotropin-releasing hormone-like agonist D-Trp6-Pro9-NEt-LHRH (LHRHa) has been shown to induce a reversible short-term suppression of gonadotropins and gonadal steroids in patients with central precocious puberty. Since accelerated statural growth and bone maturation are clinical features of precocity not well controlled by conventional therapies, we examined the effects of prolonged LHRHa therapy for 18 consecutive months on growth and skeletal maturation in nine girls with neurogenic or idiopathic precocious puberty. Suppression of gonadotropin pulsations and gonadal steroids was maintained in all subjects. Growth velocity fell from a mean rate (+/- S.E.M.) of 9.35 +/- 0.64 cm per year during the 19 months before treatment to 4.58 +/- 0.60 cm per year during treatment (P less than 0.001). Bone age advanced a mean of 9.4 +/- 2.3 months during treatment. These changes resulted in a mean increase of 3.3 cm in predicted height (P less than 0.01). Complete suppression of the pituitary-gonadal axis can be maintained by LHRHa therapy, resulting in slowing of excessively rapid growth and skeletal maturation and in increased predicted adult height in girls with precocious puberty.

Age Determination by Skeleton↗
PubMed1983

Extended MHC haplotypes in 21-hydroxylase-deficiency congenital adrenal hyperplasia: shared genotypes in unrelated patients.

HLA, complement, and glyoxalase I alleles were studied in 29 families in which at least one member has classical 21-hydroxylase-deficiency congenital adrenal hyperplasia. A rare complement allele, C4B*31, was found in over 20% of the haplotypes defined in these families and was always part of the complement haplotype BF*F, C2*C, C4A*Q0, C4B*31 (abbreviated FCO,31). The haplotype containing this rare set of complement alleles always carried the rare HLA allele, HLA-Bw47, usually carried HLA-A3, and almost always had the alleles HLA-Cw6, HLA-DR7, and the glyoxalase I (GLO) allele GLO1. Thus over 20% of the haplotypes in the population studied contained all or almost all of the rare extended haplotype HLA-(A3), Bw47, Cw6,DR7, FCO,31, GLO 1. 3 other haplotypes were each found twice in unrelated patients concordant for their disease phenotype and ethnic background. Extended MHC haplotypes may be markers for different genetic mutations causing 21-hydroxylase deficiency.

Adrenal Hyperplasia, Congenital↗
PubMed1983

Detection of late-onset 21-hydroxylase deficiency congenital adrenal hyperplasia in adolescents.

Because severe hirsutism is difficult to reverse, the evaluation of the adolescent girl with progressive hirsutism should aim at the pathophysiology of androgen excess in order to select appropriate therapies. A prospective study was undertaken to determine the occurrence of late-onset 21-hydroxylase deficiency among adolescents with androgen excess. Twenty-two young women (mean age 17.3 +/- 2.6 years) with androgen excess had serum 17-hydroxyprogesterone measured before and after bolus intravenous infusion of synthetic ACTH (Cortrosyn), 0.25 mg. Two patients, aged 13 and 19 years old, had elevated base line 17-hydroxyprogesterone and 30- and 60-minute responses to Cortrosyn consistent with 21-hydroxylase deficiency. Chromosome 6p haplotypes provided supportive evidence of 21-hydroxylase deficiency. The base line androgen levels, clinical presentation, and a four-day dexamethasone test did not distinguish patients with 21-hydroxylase deficiency from other hirsute adolescents. The Cortrosyn test identifies a population of adolescents who need long-term corticosteroid therapy. The use of major histocompatibility complex haplotypes could be of help in identifying affected siblings prior to the development of significant hirsutism.

Adolescent↗
PubMed1981

Granulosa theca cell tumors in premenarchal girls: a clinical and pathologic study of ten cases.

Granulosa theca cell tumor (GTCT) in the premenarche accounted for 7% of all ovarian tumors treated at the Children's Hospital Medical Center from 1928 through 1979. The average age of the ten girls at the time of diagnosis was 5 years (range 11 months-121/2 years) with precocious "pseudopuberty" and an abdominal mass being the most common presentation. GTCTs were solitary (five right, five left) with an average diameter of 12.1 cm. Histologic examination showed a predominantly diffuse or solid pattern with prominent luteinization; Call-Exner bodies and folded ("coffee-bean") nuclei were inconspicuous. Ultrastructural examination of one GTCT confirmed the presence of both granulosa and theca components with the latter showing extensive luteinization; estradiol, testosterone and prolactin were demonstrated in the same tumor using immunologic techniques. The average follow-up time was 21 years with nine of the ten patients being followed for more than ten years. Salpingo-oophorectomy resulted in cures despite the occurrence of tumor spillage in two patients. The prognosis for GTCTs in the premenarche appears more favorable than for those occurring in adulthood, but further study is needed to completely define their full biologic potential; the significance of subsequent breast cancer in two long-term survivors merits further investigation as well.

Basement Membrane↗
PubMed1978

A virilizing adrenocortical tumor in a female infant: in vivo and in vitro biochemical characteristics.

Normal adrenal and adrenal tumor cells from a female infant with a virilizing adrenal tumor were grown in tissue culture as monolayers for a period of 7 weeks. Half of the cultures were exposed to ACTH (0.1 U/ml). The cells grew well and continued to produce steroid hormones over the entire period in culture. Production of steroid hormones was measured by RIA of individual steroids in the culture medium. Unstimulated normal and tumor cells produced equivalent amounts of cortisol, 11 beta, 18, 21-trihydroxy-4-pregnene-3,20-dione, and 18,21-dihydroxy-4-pregnene-3,20-dione, but tumor cells produced lesser amounts of dehydroepiandrosterone (DHA), androstenedione, testosterone, and progesterone. Normal cells exposed to ACTH showed an increase in all steroids measured, whereas ACTH-exposed tumor cells showed an increase principally in DHA consistent with a deficiency in 3 beta-hydroxysteroid dehydrogenase activity. Circulating levels of DHA, androstenedione, and testosterone were elevated in the patient before removal of the adrenal tumor. The production of androgens by tumor cells in vitro resembled the pattern of circulating steroids in vivo. These studies demonstrate that tissue culture of human adrenal cells provides a means both to determine their biochemical characteristics and to investigate their responses to exogenous hormones.

Adrenal Cortex↗
PubMed1977

Hypoglycemia of infancy and nesidioblastosis. Studies with somatostatin.

We treated a two-month-old infant with servere intractable hypoglycemia and nesidioblastosis with continuous glucose infusions (0.75 g per kilogram per hour) via a central venous catheter. Preprandial glucose levels on this regimen were 37+/-2 mg per deciliter (+/-S.E.M.). Basal serum insulin levels were within normal fasting levels for this age group but inappropriately elevated for the blood glucose levels. The beta cells were exquisitely sensitive to infusions of synthetic cyclic somatostatin, with a dose-dependent rise in blood glucose and concomitant suppression of serum insulin levels. There was only minimal suppression of plasma glucagon levels. Single subcutaneous injections of 50 microng of protamine zinc somatostatin raised preprandial blood glucose levels to 83+/-3 mg per deciliter for four to five days although preprandial hormone levels were unchanged. These findings indicate that hypoglycemia of infancy is a hyperinsulin state with abnormal basal regulation of insulin secretion.

Adenoma, Islet Cell↗
PubMed1977

Glycogen storage disease: new approaches to therapy.

Detailed studies of the effect of 32 days of intravenous alimentation on the metabolic, hormonal and clinical status of a 4-year-old boy with Type I glycogenosis revealed that the biochemical abnormalities and growth failure in this disorder are a consequence of glucose lack after brief periods of fasting which results from the inborn enzyme deficiency. Long-term (1.5-5.7 years) observations of the therapeutic effects of portacaval shunt without and with continuous overnight intragastic glucose by gastrostomy in two brothers, and of continuous overnight intragastric glucose alone in five other patients with this disorder, on metabolic status and physical growth and development suggest that adequate glucose can be provided by the intragastric route without hepatic portal circulatory by-pass. The introduction of this therapy in the first year of life should prevent the serious risk to life and long-term failure in growth and development previously observed in patients with Types I and III glycogenosis.

Child↗