Faculty Bibliography

Congenital lipoid adrenal hyperplasia is an autosomal recessive disorder that is characterized by impaired synthesis of all adrenal and gonadal steroid hormones. In three unrelated individuals with this disorder, steroidogenic acute regulatory protein, which enhances the mitochondrial conversion of cholesterol into pregnenolone, was mutated and nonfunctional, providing genetic evidence that this protein is indispensable normal adrenal and gonadal steroidogenesis.

Congenital lipoid adrenal hyperplasia (lipoid CAH) is a rare genetic disorder of adrenal and gonadal steroidogenesis of unknown cause in which cholesterol cannot be converted to pregnenolone. As a result, affected individuals can make no steroid hormones, so that all affected newborns are phenotypic females, irrespective of karyotype. We studied two pregnancies in a family with two previously affected children by examining fetal karyotype, genital ultrasonography, and amniotic fluid steroid concentrations and by performing ACTH tests on family members. Prenatal diagnosis correctly identified both an unaffected XX fetus and an affected XY fetus. In the affected pregnancy, amniotic fluid concentrations of progesterone and pregnenolone were 30% and 50% of normal, respectively, but concentrations of 17 alpha-hydroxypregnenolone, 17 alpha-hydroxyprogesterone, cortisol, dehydroepiandrosterone, androstenedione, and estriol were either extremely low or undetectable, suggesting that these detected steroids were donated by maternal steroidogenesis. Fetal cord blood obtained at the termination of pregnancy showed very low concentrations of estrogens donated by the mother's circulation. Absent fetal steroidogenesis was confirmed by gas chromatography and mass spectrometry of both fetal and maternal serum. The responses of 10 different steroids to adrenal stimulation with ACTH in the obligately heterozygous parents were normal. Thus, unlike the case with other forms of CAH, heterozygosity cannot be determined by hormonal responses to provocative testing with ACTH. Immunocytochemistry and Western blotting showed that the affected placental tissue contained P450scc protein, confirming that P450scc is intact in these patients.

Functional ovarian hyperandrogenism (FOH) is characterized by an abnormal ovarian response to challenge with the GnRH analogs nafarelin and leuprolide acetate, similar to that observed in women with well defined polycystic ovary syndrome, regardless of whether elevated LH levels or polycystic ovaries are present. We studied an unselected group of 42 hyperandrogenic adolescents (age range, 14-22 yr; mean, 18.1 +/- 2.5 yr) 1) to determine FOH incidence through the assessment of ovarian-steroidogenic response to a single dose of leuprolide acetate, 2) to assess the clinical characteristics of patients according to their responses to GnRH analog stimulation, and 3) to evaluate adrenal steroidogenic function and its relation to ovarian hyperandrogenism in patients with either normal or abnormal responses to leuprolide acetate challenge. All patients underwent leuprolide acetate and ACTH testing, dexamethasone and ovarian suppression tests, and pelvic ultrasonography. Twenty-four (58%) patients had supranormal plasma 17-hydroxyprogesterone (17-OHP) responses to leuprolide acetate characteristic of FOH, and in 18, the 17-OHP response was similar to that of controls (n = 24; age, 17.1 +/- 2.3 yr). Seven patients (5 with FOH and 2 with normal responses to leuprolide acetate) had an abnormal response to ACTH, but only 1 had conclusive evidence of 21-hydroxylase deficiency. In 16 patients, the response to both stimulation tests was normal. Only 13 (54%) of the 24 FOH patients had polycystic ovaries on ultrasonography, and in 11 (46%), basal plasma LH levels were elevated. In FOH patients, reduction in testosterone and androstenedione plasma levels was significantly greater after ovarian suppression than after dexamethasone challenge (P < 0.0005 and P < 0.02, respectively). Peak plasma 17-OHP levels postleoprolide acetate simulation correlated with dexamethasone-suppressed plasma testosterone concentrations, dexamethasone-suppressed plasma androstenedione levels, and the free androgen index postdexamethasone treatment (r = 0.4, P = 0.01; r+ 0.4, P < 0.05; and r = 0.41, P = 0.007, respectively), Plasma sex hormone-binding globulin levels after dexamethasone administration correlated negatively with the baseline free androgen index (r = -.0.67; P < 0.0001). Considering our diagnostic criteria, 26 (62%) of our collective of 42 patients had abnormal responses to one or both stimulation tests, whereas 16 (37%) had normal response. FOH is the most common cause in (58%) of androgen excess in adolescence. Short term leuprolide acetate stimulation is a reliable tool fro identification of the ovary as the source of their hyperandrogenism.

OBJECTIVE: A link between serum testosterone and aggressive behavior, which has been demonstrated in numerous animal studies and suggested in several studies of adult men, has never been investigated in children before the time of puberty. METHOD: We measured serum testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS) in 18 highly aggressive prepubertal boys, ages 4 to 10, hospitalized for violent or unmanageable behavior at a state children's psychiatric facility in New York City (the Bronx). We compared them with a group of age and race matched controls from the same demographic area, screened negative for aggressive behavior problems. All the aggressive subjects met DSM-III-R criteria for conduct disorder and scored higher than the 98th percentile on the aggression subscale of the Child Behavior Checklist (mean T = 80 for the group). RESULTS: There were no significant differences between aggressive and nonaggressive children for T, SHBG, DHEA, DHEAS, or ratios of combinations of these variables. CONCLUSIONS: These findings raise questions about inferences from adult studies that testosterone may play a causal role in the development of human aggression. Testosterone does not appear to be a useful biological marker for aggressivity in early childhood.

The TSH response to TRH administration (7 micrograms/kg) was measured in 68 infants (22 premature) who had abnormal thyroid screening tests by the filter paper method and whose serum thyroid function tests were only mildly abnormal. Twenty-eight infants (12 premature) had peak TSH values of 35 mU/L or less and were considered normal (group I). Forty infants (10 premature) had peak TSH values above 35 mU/L and were considered hyperresponsive (group II). The mean age at testing, screening T4, TSH levels that prompted the testing, as well as baseline T4, T3, and free T4 at the time of TRH testing were not different between the groups. The mean (+/- SD) baseline TSH value was greater in group II (6.8 +/- 2.3 mU/L) than in group I (4.4 +/- 2.2 mU/L; P < 0.001). However, there was a great deal of overlap in the individual TSH values (group I, 0.9-10 mU/L; group II, 1.9-10.6 mU/L). Mean peak TSH levels were significantly different in the two groups (group I, 24 +/- 7.7 mU/L; group II, 60.3 +/- 26.1 mU/L; P < 0.001). During long term follow-up, all 25 group I infants available for evaluation have been confirmed as clinically and biochemically normal. No infant diagnosed as normal was later found to have evidence of hypothyroidism. Fourteen infants in group II have had evidence of thyroid dysfunction. We conclude that the TSH response to TRH stimulation is a useful tool for the evaluation of infants suspected of having primary hypothyroidism. Whether hyperresponsiveness to TRH represents a form of neonatal hypothyroidism requiring treatment remains to be determined.

Velocardiofacial syndrome (VCF) has overlapping features with DiGeorge sequence; both result from a developmental field defect and probably represent contiguous gene deletion syndromes. The association of chromosome 22q11 deletion with DiGeorge sequence led us to do molecular analysis of chromosome 22 in 18 patients with VCF, who ranged in age from 6 to 42 years. All 18 patients had monosomy for the chromosome region 22q11. Retrospectively, we correlated the presence of the deletion with various clinical findings: 100% had cleft palate, 67% the facial phenotype, 83% cardiac disease, 94% learning disabilities, 70% ophthalmologic findings, 50% short stature, 22% psychiatric disorders, and 17% hypocalcemia. Both severely phenotypically affected and mildly affected patients had the deletion. These findings stress the importance of continued surveillance of all patients with VCF for the many medical problems that may not be present at initial diagnosis. We conclude that the presence of the gene deletion does not predict the phenotypic expression in VCF. Further studies to characterize the size of the gene deletion may facilitate better prediction of the phenotype.

Adult HBV-transgenic males produce more hepatitis B surface antigen (HBsAg) in serum than females. The difference decreases with castration and is restored with testosterone replacement. To investigate the contribution of the androgen receptor in this process, HBV-transgenic males were mated with females heterozygous for the testicular feminization mutation (Tfm), an X-linked gene with 90% reduced androgen receptor. A total of 19 phenotypic HBV-transgenic females were studied, of which eight XYTfm females were identified by the presence of Y-chromosome DNA using molecular hybridization. The 11 normal (XX) females had 11.7 +/- 3.5 micrograms/mL (mean +/- SD) of HBsAg in their serum, whereas the Tfm (XY) females had 17.1 +/- 5.9 micrograms/mL (p < 0.05). However, the Tfm (XY) females produced less HBsAg than 33 normal (XY) males (41 +/- 12 micrograms/mL), and the overall ratio of male/female HBsAg levels was reduced: XY/XX = 3 versus XYTfm/XX = 1.5. Although dexamethasone caused an increase in XYTfm and XX mice, testosterone did not increase HBsAg in XYTfm. These data indicate that hepatitis B expression as measured by HBsAg levels in this animal model is mediated through an androgen receptor.