Neuropsychological functioning in girls with premature adrenarche.

Contemporary research indicates that brain development occurs during childhood and into early adulthood, particularly in certain regions. A critical question is whether premature or atypical hormone exposures impact brain development (e.g., structure) or function (e.g., neuropsychological functioning). The current study enrolled 40 girls (aged 6-8 years) diagnosed with premature adrenarche (PA) and a comparison group of 36 girls with on-time maturation. It was hypothesized that girls with PA would demonstrate lower IQ and performance on several neuropsychological tasks. The potential for a sexually dimorphic neuropsychological profile in PA was also explored. No significant univariate or multivariate group differences emerged for any neuropsychological instrument. However, effect size confidence intervals contained medium-sized group differences at the subscale level. On-time girls performed better on verbal, working memory, and visuospatial tasks. Girls with PA showed improved attention, but not a sexually dimorphic profile. These results, though preliminary, suggest that premature maturation may influence neuropsychological functioning.

Treatment to near adult stature of patients with myelomeningocele with recombinant human growth hormone.

UNLABELLED: We evaluated near adult statural outcome of treating growth hormone (GH) deficient children (peak GH values <10 ng/ml) with myelomeningocele (MMC) with 0.3 mg/kg/week of recombinant human GH. Retrospective evaluation of 20 patients (12 males) who were consistently measured using recumbent length and who had achieved more than 90% of their adult stature on GH treatment were included. Pretreatment scoliosis was present in 13 patients (<30 degrees); 16 patients had lumbar level of lesion, while four had sacral level of lesion; 19 of 20 had a ventriculoperitoneal shunt. During GH treatment, two girls were successfully treated with leuprolide acetate for precocious puberty, two patients were concurrently treated for hypothyroidism and were euthyroid. Standard deviation score (SDS) for recumbent length at near adult stature increased in comparison to the general adult population and untreated adults with MMC (-2.6 to -1.4 and +0.6, respectively, p <0.001). Fifteen of 20 patients at near adult stature were above the 3rd percentile of current United States growth charts. These patients were less overweight as body mass index (BMI) was less than untreated shorter adults with MMC (p <0.01 for females, <0.001 for males). Scoliosis did not progress. CONCLUSION: Near adult stature for GH-treated children with MMC is significantly greater than untreated adults with MMC. Relative obesity is decreased with significant improvement of BMI. This is the first report of statural outcome near completion of growth for GH-treated children with MMC.

Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche: potential implications of a preliminary study.

Premature adrenarche is a condition characterized by precocious development of pubic and/or axillary hair, due to early onset of adrenal androgen secretion. Girls with premature adrenarche may later develop menstrual irregularities, hyperandrogenism, and the classic polycystic ovary syndrome. As leptin is thought to modulate the onset of pubertal development, we measured plasma leptin levels in 7 girls with premature adrenarche, and 8 age-matched comparison girls. Because leptin, the hypothalamic-pituitary-adrenal (HPA), the hypothalamic-pituitary-gonadal axes are functionally interrelated, we also determined salivary and plasma cortisol, dehydroepiandrosterone (DHEA), DHEA-sulfate, androstenedione, estradiol, and estrone. Finally, since IGF-I may play a role in adrenocortical function, we determined plasma levels of IGF-1, and IGF-BP1. Plasma was collected by an intravenous catheter at times 0, 20, and 40 min, starting at 1.30 p.m. Girls with premature adrenarche had a higher body mass index (BMI) and an over two-fold elevation of their plasma leptin than comparison girls. This group also had elevated levels of salivary and plasma cortisol, and increased levels of DHEA, DHEA-S, androstenedione, estradiol and estrone. Plasma IGF-1 and the ratio of IGF-1/IGF-BP1 were elevated. We propose that girls with premature adrenarche may represent an overlapping group characterized by both features of increased adiposity and HPA axis activity, which together, and depending on the genetic/constitutional background of the individual, may account for the development of adrenal hyperandrogenism, and, later, the polycystic ovary syndrome.

Biopsychological and cognitive differences in children with premature vs. on-time adrenarche.

BACKGROUND: Puberty consists of 2 components: gonadarche and adrenarche. Both components have distinct endocrine changes. Adrenarche has virtually been ignored with respect to examining hormone-behavior relations. OBJECTIVES: To provide descriptive biological and behavioral information on children with premature adrenarche (PA) and to examine differences in biological, psychological, and cognitive variables of children with PA and a healthy comparison group of children with on-time adrenarche. DESIGN: Descriptive pilot study. SETTING: A consecutive sample of patients was recruited from pediatric endocrine clinics; comparison children were recruited from the community. PARTICIPANTS: Children aged 6 to 9 years. Mean (+/-SD) age of children with PA (n = 9) was 7.8 (+/-1.3) years; of children with on-time adrenarche (n = 20), 8.0 (+/-1.2) years. METHODS AND MEASURES: Serum and saliva samples were collected for measurement of hormone concentrations. Questionnaires, tests, and interviews were completed by children and parents. RESULTS: Compared with the on-time group, the PA group had significantly higher concentrations of adrenal androgens, estradiol, thyrotropin, and cortisol. By parent report on the Diagnostic Interview Schedule for Children, 4 children (44%) met diagnostic criteria for psychological disorders (primarily anxiety disorders). The PA group also had more self-reported depression and parent-reported behavior problems and lower scores on various intelligence tests. CONCLUSIONS: Although PA is considered a normal variation of pubertal development that warrants no medical intervention, PA presents with significant psychosocial problems. Children with PA may need psychological evaluation and follow-up. Future studies should confirm these findings with a larger sample and examine the long-term ramifications of this early presenting abnormality.

Growth hormone treatment of children with myelomeningocele.

From the National Cooperative Growth Study database 106 patients (53 boys) with myelomeningocele who were treated with recombinant human growth hormone (GH) at 56 centers were identified. Eighty-one patients (41 boys) were prepubertal at enrollment. The mean pretreatment growth rate (GR) in these prepubertal patients was 4.5 +/- 3.7 cm/yr, and the mean height SD score was -4.0 +/- 1.2. The maximal stimulated GH level was less than 10 micrograms/L in 71% of these patients and less than 7 micrograms/L in 49%. The mean chronologic age was 6.5 +/- 2.9 years, and the mean height age was 3.7 +/- 1.7 years. After GH treatment the year 1 GR in those who remained prepubertal was 8.5 +/- 3.3 cm/yr, a significant increase over baseline (p < 0.01). This increase was sustained through year 4 and remained significant through year 3 (p < 0.01). The height SD score showed sustained significant improvement through year 4, to -2.2 +/- 1.4 (p < 0.001). The GR and SD score for stature improve with GH treatment in children with myelomeningocele.

Growth hormone treatment of children with neural tube defects: results from 6 months to 6 years.

OBJECTIVE: Patients with neural tube defects (myelomeningocele) have severe growth retardation, and treatment with recombinant human growth hormone (rHGH) for 6 months accelerates growth velocity. We examined patients treated for longer periods to determine whether accelerated growth persists, and whether patients demonstrated to be growth hormone deficient have a greater response to rHGH therapy. METHODS: We retrospectively evaluated the growth rate and length standard deviation score (SDS) of 22 patients in response to treatment with 0.3 mg/kg per week of rHGH for 7 to 72 months. Nine of 22 patients were growth hormone deficient (nocturnal and provocative growth hormone responses < 7 ng/ml). Treatment success was defined as an increase of length SDS of > 0.2 SD per year. RESULTS: Fourteen patients (64%) had treatment successes, and eight had treatment failures. Length SDS improved from a pretreatment value of -2.9 (+/- 1.2) to the most recent length SDS of -1.9 (+/- 1.4) (p < 0.001). The growth rate was significantly increased through year 4 of treatment. The annualized growth rate after 6 months of rHGH treatment was significantly different for the success and failure groups (11.0 +/- 2.6 cm/yr vs 5.1 +/- 3 cm/yr, p < 0.001). The annualized 6-month growth rate during treatment was related to the probability of treatment success. CONCLUSION: Treatment with rHGH significantly improves the growth rate and length SDS of children with neural tube defects. The 6-month annualized growth velocity during treatment was predictive of long-term treatment response. The effect on adult stature is unknown.

Growth of growth hormone-treated and nontreated children before and after tethered spinal cord release.

Children with myelomeningocele (MM) are very short and respond to treatment with recombinant human growth hormone (RHGH) with an acceleration in growth. Following primary closure of the MM, a tethered spinal cord may produce neurologic and orthopedic deformities. We compared the short-term growth rate and length standard deviation score (L-SDS) for stature of 13 prepubertal children with MM (7 males, 6 females, mean age 6.1 +/- 2.5 years) before and after symptomatic tethered spinal cord release (TCR) to an untreated asymptomatic matched control group. We also compared these data to 7 prepubertal children with MM and growth hormone inadequacy who had TCR and were then treated with RHGH. TCR significantly increased the growth rate compared with matched controls (p < 0.01); however, TCR and RHGH in combination provided an increased gain in growth rate and L-SDS over TCR alone (p < 0.01). Tethered spinal cord influences the growth rate of children with MM. Further study is necessary to evaluate the relationship of the tethered spinal cord to growth and treatment of growth failure.

Adult stature and anthropomorphic measurements of patients with myelomeningocele.

UNLABELLED: Children with myelomeningocele are extremely short, yet little data exists on adult stature and anthropomorphic measurements. We measured the recumbent length, weight, arm length, sitting height and calculated body mass index of 54 adults with myelomeningocele. Mid parental height was also calculated. Measurements were compared with normative data. Patient charts were reviewed for history of hydrocephalus. The 27 males and 27 females had a mean age of 24.8 +/- 5.7 years. The mean length for adult females was 141.9 +/- 12 cm and was 152.1 +/- 13 cm for males. Patients with thoracic level of lesions were shorter than those with lumbar level who were, in turn, shorter than those with sacral levels. Recumbent length, sitting height, arm length and arm span were significantly smaller than expected values. Recumbent length was smaller than mid parental height. Those with ventriculoperitoneal shunts, required for hydrocephalus, were shorter than these without a shunt. CONCLUSION: Adults with myelomeningocele have significant short stature. Arm span is not an interchangeable measure with length for patients with myelomeningocele. Multiple factors are likely to be responsible for the observed short stature.

Change in spinal curvature following release of tethered spinal cord associated with spina bifida.

Changes in spinal curvature, scoliosis, kyphosis and lordosis are associated with the growth of patients with myelomeningocele. Previous investigators have stated that progressive developmental scoliosis is related to tethered spinal cord. In order to investigate the relationship of tethered spinal cord release to progression of spinal curvature, we surveyed the medical records of 262 patients with a history of one or more tethered spinal cord release. For 216 of these patients, a total of 2,369 serial spine x-rays, obtained over a 20-year period, were reviewed by the standard Cobb method for progression of scoliosis, thoracic kyphosis and lordosis. In addition, the serial spine x-rays of 74 patients without clinical findings of tethered spinal cord were collected and reviewed for comparison of progressive scoliosis and kyphosis. One hundred and sixty normal lumbar x-rays were evaluated to compare the progression of the lordotic curve in patients with tethered cord release with a normal population. Progression of scoliosis plateaued or declined following release of tethered cord in patients with lumbar and sacral level lesions, however, tether release did not halt the progression of scoliosis in the thoracic level group. Tethered cord release altered the course of lordosis in L1 through L3 level lesions, but had little affect on the normal progression of lordosis in patients with L4, L5 or sacral level lesions. Finally, tethered spinal cord release appears to be associated with a decrease in the incidence and magnitude of kyphosis.

Palliative treatment of hyperinsulinism with cyproheptadine and diazoxide.

Treatment for hyperinsulinism in infants and children can be difficult and has included numerous treatment modalities. This paper reports 16 months of palliative treatment with cyproheptadine and diazoxide in a child with hyperinsulinism initially diagnosed at 6 months of age (her insulin level was 80 microU/mL while her glucose level was 38 mg/dL). She continued to have episodes of staring and alteration in level of consciousness while receiving her usual doses of diazoxide (12 mg/kg) alone. Mean nocturnal glucose values, which were quite low during treatment with diazoxide alone, improved significantly with the addition of cyproheptadine to her therapeutic regimen. Fasted C-peptide values, elevated during diazoxide alone, returned to the normal range with combination treatment for 16 months. Cyproheptadine and diazoxide in combination may be useful for treatment of hyperinsulinism that presents after the neonatal period.

Binding of activated progesterone receptor to microsomes.

Specific binding of steroid hormones to microsomes has been reported for several tissues. In the hen oviduct, this receptor appears to be very similar to activated cytosolic receptor. The microsomal receptor is readily solubilized, and resembles the cytosolic receptor in all physico-chemical characteristics: sedimentation coefficient approximately 4 S, Stokes radius 5.5 nm, slow dissociation rate of the complex, adsorption to polyanions. It is precipitated by an antibody to the cytosolic receptor. Microsomes display saturable binding of cytosolic receptor, with a Bmax of approximately 300 fmol/mg protein. This binding is also observed using microsomes from non-target tissues, and is decreased by treatment with RNase. It seems likely that microsomal binding is due to the high affinity of activated cytosolic receptor for RNA.

Cyanoketone competition with estradiol for binding to the cytosolic estrogen receptor.

Cyanoketone, an inhibitor of many steroidogenic processes, has been found to inhibit binding of estradiol to its receptor in a competitive manner. The Ki observed was 1.2 X 10(-6)M. This action may explain some of cyanoketone's effects in vivo.