Androgen-responsive aspects of cognition in girls with Turner syndrome.

Turner syndrome (TS) represents a unique, sex hormone-deficient model in which to study the biological effects of androgen treatment (replacement) on cognition in females because TS girls have gonadal dysgenesis and absent ovarian androgen and estrogen production. We investigated the effects of androgen replacement therapy in TS girls, ages 10-14 yr, on cognitive function. A total of 64 TS girls were randomized to receive oxandrolone or placebo for 2 yr. They had a cognitive evaluation of four domains (verbal abilities, spatial cognition, executive function, and working memory) at baseline, 1, and 2 yr of the study. In addition, all subjects were examined for study safety every 6 months. Three of the four domains studied did not change significantly in response to oxandrolone treatment (verbal abilities, spatial cognition, and executive function). In contrast, the working memory summary score had a significant group by time interaction. The oxandrolone-treated group demonstrated improved performance after 2 yr, compared with the placebo group (P < 0.03). Minimal or no side effects were observed. In conclusion, oxandrolone treatment for 2 yr improves working memory in adolescent girls with TS. What this degree of improvement will mean in real life terms for TS girls remains to be determined.

Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience.

We report 98 children who have reached final adult height in a long-term trial of LHRH agonist treatment. These children were 5.3 +/- 2.1 yr old at the start of treatment and were treated with either deslorelin (4 microg/kg.d sc) or histrelin (4-10 microg/kg.d) for an average of 6.1 +/- 2.5 yr. Final height averaged 159.8 +/- 7.6 cm in the 80 girls, which was significantly greater than pretreatment predicted height (149.3 +/- 9.6 cm) but still significantly less than midparental height (MPH) (163.7 +/- 5.6). Final height averaged 171.1 +/- 8.7 cm in the 18 boys, which was significantly greater than pretreatment predicted height (156.1 +/- 14.2 cm) but still significantly less than MPH (178.3 +/- 5.2 cm). However, the average adult height of the 54 children who had less than a 2-yr delay in the onset of treatment was not significantly different from their MPH, and 21 children exceeded MPH. Final height SD score correlated positively with duration of treatment (P < 0.01), midparental height (P < 0.001), predicted height at the start of treatment (P < 0.001), and growth velocity during the last year of treatment (P < 0.001) and correlated inversely with delay in the onset of treatment (P < 0.001), age at the start of treatment (P < 0.001), bone age at the start of treatment (P < 0.001), bone age at the end of treatment (P < 0.001), breast stage at the start of treatment (P = 0.02), and bone age minus chronological age at the start of treatment (P = 0.001). We conclude that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 yr for girls or 9 yr for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronological and bone age at the onset of treatment all lead to greater final height. All children with onset of pubertal symptoms before age 8 in girls and age 9 in boys should be evaluated for possible treatment. Treatment is appropriate in children with rapidly progressing puberty, accelerated bone maturation, and compromise of adult height prediction, regardless of bone age or chronological age at time of evaluation. However, once treatment is considered appropriate, it should be initiated quickly, because longer delays lead to shorter final height. In addition, the longer the treatment is continued, the greater is the final height outcome.

Evidence for decreased growth hormone in patients with hypothalamic hamartoma due to Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) is characterized by hypothalamic hamartoma, bifid epiglottis, and central or postaxial polydactyly. Familial transmission is autosomal dominant; isolated cases also occur. To screen for hypothalamic-pituitary dysfunction in PHS, we studied a 12 year-old boy (patient #1), and 14 additional patients (patients #2-14: 7M, 7F; ages 4-72 yr). We performed serial sampling of GH, LH/FSH, TSH, and cortisol from 20.00-08 00 h. At 08.00 h, we measured IGF-I, peak responses of LH and FSH after GnRH, and cortisol after ACTH. We found that 6/7 children, including patient #1, and 6/8 adults had low or absent spontaneous GH secretion and/or low levels of IGF-I. Patient #1 also had accelerated pubertal development, but no other patient had abnormalities of the pituitary-gonadal axis, and none of the 14 patients had an abnormal thyroid or adrenal axis. We conclude that decreased pituitary GH secretion is common in PHS, and may exist in the absence of other forms of endocrine dysfunction.

Psychosocial development in adolescents with Turner syndrome.

Turner syndrome is a genetic condition in which part or all of the second X chromosome is missing. Our goal in this study was to examine the psychosocial adjustment of a sample of adolescent girls with Turner syndrome. Subjects included 122 girls with a diagnosis of Turner syndrome (TS) and a control group of 108 girls with no genetic disorder or chronic illness. Subjects were 13 to 18 years of age. A battery of questionnaires assessing social, academic, school, and behavioral functioning was administered. TS girls were seen as having significantly more problems in terms of social relationships and school progress and were more likely to meet criteria for attention-deficit hyperactivity disorder than control girls. The TS girls were also rated by a parent as less socially competent (e.g., fewer friends, less time with friends) than the control group. Social difficulties appear to be an area of vulnerability for TS girls. Counseling individuals with Turner syndrome and their families about the need to carefully develop and nurture social skills and relationships may prove useful in advancing the social adaptation of these young women.

Boys with precocious puberty due to hypothalamic hamartoma: reproductive axis after discontinuation of gonadotropin-releasing hormone analog therapy.

Hypothalamic hamartoma is an important cause of precocious puberty in boys. Although the GnRH analogs are known to be effective therapy, there are few studies of the recovery of the pituitary-gonadal axis following long-term treatment. To this end, we studied 11 boys with HH after 8.8+/-3.2 yr (range, 4.0-12.6) of treatment with the GnRH agonist D-Trp6,Pro9,NEt-LHRH. The patients' levels of LH and FSH, testosterone, testis volume, and body mass index were compared with those of six normal boys in pubertal stage IV-V. We found that the patients' mean +/- SD peak GnRH-stimulated LH and FSH had returned to the normal range by 1 yr after stopping therapy. Whereas testosterone returned to normal levels by 1 yr, the patients' testis volume remained smaller than normal until 2 yr after therapy. Ultrasonography revealed diffuse, punctate, echogenic foci in the testicular parenchyma of two patients; these were first observed during GnRH agonist therapy and persisted unchanged after discontinuation of treatment. Neither of these two patients reported pain or testicular discomfort, no mass or irregularity was detected by manual examination in either patient at any time, and levels of beta-hCG and alpha1-fetoprotein were normal. By 4 yr after therapy, all patients had pubertal stage V pubic hair; their body mass index was not different from that of the normal boys at any time point. The dimensions of the patients' hamartomas did not change during or after therapy, and no patient reported new neurological symptoms or signs suggestive of an enlarging lesion at any time during or after discontinuation of treatment. Two families did report episodes of emotional lability and truancy as the patients reentered puberty after discontinuation of treatment.

Use of estrogen in young girls with Turner syndrome: effects on memory.

BACKGROUND: The Turner syndrome (TS) phenotype is characterized by a specific neurocognitive profile of normal verbal skills, impaired visual-spatial and visual-perceptual abilities, and impaired nonverbal more than verbal memory. We compared verbal and nonverbal memory in estrogen- and placebo-treated girls with TS (ages 7 to 9 years) and age-matched female controls. METHODS: Children received either estrogen (ethinyl estradiol, 25 ng/kg/d) or placebo for 1 to 3 years (mean, 2.1+/-0.9 years) in a randomized, double-blind study. Memory and language tasks administered included the Wechsler Intelligence Scale for Children-Revised, Digit Span (forward and backward), the Children's Word List, the Denman Paragraph, the Peabody Picture Vocabulary Test, Boston Naming, immediate and delayed Recall of the Rey Complex Figure, Nonword Reading, Wide Range Achievement Test-Revised reading subtest, Verbal fluency, and the Token Test. RESULTS: The estrogen-treated TS group performed better than the placebo-treated TS group for the Children's Word List immediate and delayed recall and the Digit Span backwards test (p<0.01 to 0.04), although the results were not significant after adjusting for multiple comparisons. The placebo-treated TS group performed less well than the controls for recall of Digit Span backward (p<0.0001; placebo-treated, 2.8+/-1.3; estrogen-treated, 3.4+/-1.2; and controls, 4.2+/-1.3) and immediate and delayed recall of the Children's Word List (delayed recall, p<0.0001; placebo-treated, 6.2+/-3.1; estrogen-treated, 8.0+/-2.9; and controls, 9.0+/-2.9). Performance for these measures was similar for the estrogen-treated TS group and the control group. CONCLUSIONS: Estrogen replacement therapy in young girls with Turner Syndrome is associated with improved verbal and nonverbal memory. The optimal patient age, dose, and duration of estrogen replacement require further study.

Reproductive axis after discontinuation of gonadotropin-releasing hormone analog treatment of girls with precocious puberty: long term follow-up comparing girls with hypothalamic hamartoma to those with idiopathic precocious puberty.

Although the GnRH agonist analogs have become an established treatment for precocious puberty, there have been few long term studies of reproductive function and general health after discontinuation of therapy. To this end, we compared peak LH and FSH after 100 microg sc GnRH, estradiol, mean ovarian volume (MOV), age of onset and frequency of menses, body mass (BMI), and incidence of neurological and psychiatric problems in 2 groups of girls: those with precocious puberty due to hypothalamic hamartoma (HH; n 18) and those with idiopathic precocious puberty (IPP; n = 32) who had been treated with deslorelin (4-8 microg/kg x day, s.c.) or histrelin (10 microg/kg x day, s.c.) for 3.1-10.3 yr and were observed at 1, 2, 3, and 4-5 yr after discontinuation of treatment. The endocrine findings were also compared to those in 14 normal perimenarcheal girls. There were no differences between the HH and IPP groups in age or bone age at the start of treatment, at the end of treatment, or during GnRH analog therapy. We found that whereas the peak LH level was higher in HH than in IPP girls before (165.5 +/- 129 vs. 97.5 +/- 55.7; P < 0.02) and at the end (6.8 +/- 6.0 vs. 3.9 +/- 1.8 mIU/mL; P < 0.05) of therapy, this difference did not persist at any of the posttherapy time points. LH, FSH, and estradiol rose into the pubertal range by 1 yr posttherapy in both HH and IPP. However, the mean posttherapy peak LH levels in both HH and IPP groups tended to be lower than normal, whereas the peak FSH levels were not different from normal, so that the overall posttherapy LH/FSH ratio was decreased compared to that in the normal girls (HH, 2.7 +/- 0.3; IPP, 2.6 +/- 0.1; normal, 5.2 +/- 4.8; P < 0.05). The MOV was larger in HH than IPP at the end of treatment (3.7 +/- 3.5 vs. 2.0 +/- 1.2 mL; P < 0.05) and tended to increase in both groups over time to become larger than that in normal girls by 4-5 yr posttherapy (HH, 14.9 +/- 12.9; IPP, 7.6 +/- 2.2; normal, 5.4 +/- 2.5 mL; P < 0.05). Whereas the onset of spontaneous menses varied widely in both groups, once menses had started, the HH group had a higher incidence of oligomenorrhea. Pelvic ultrasonography revealed more than 10-mm hypoechoic regions in 4 HH patients, 15 IPP patients, and 3 normal girls, all of whom were reporting regular menses. Live births of normal infants were reported by 2 HH and 2 IPP patients, and elective terminations of pregnancy were reported by 1 HH and 2 IPP patients. BMI was greater than normal in HH and IPP both before treatment and at all posttherapy time points and tended to be higher in the HH patients. Marked obesity (BMI, +2 to +5.2 SD score) was observed in 5 HH and 6 IPP patients, 1 of whom had a BMI of +2.5 SD score and developed acanthosis nigricans, insulin resistance, and hyperglycemia. Seizure disorders developed during GnRH analog therapy in 5 HH and 1 IPP patient, and 2 additional HH girls developed severe depression and emotional lability posttherapy. Although the mean anterior-posterior dimension of the hamartoma was larger in the HH patients with seizure than in those who were seizure free (1.7 +/- 1.2 vs. 0.9 +/- 0.4 cm; P < 0.05), no change in hamartoma size was observed either during or after therapy, and no patient has reported the onset of a seizure disorder posttherapy. Other than a tendency toward a larger MOV, a higher incidence of oligomenorrhea, obesity, and frequency of neurological disorders, recovery of the reproductive axis after GnRH analog therapy was not markedly different in HH compared to IPP. Continued follow-up of these patients may determine whether the decreased LH responses and increased BMI in both groups compared to those in normal girls remain clinically significant problems.

Use of aromatase inhibitors in precocious puberty.

During puberty, estrogen causes breast maturation and growth of the uterine lining in girls, and accelerates linear growth and bone maturation in both boys and girls. Decreasing the biosynthesis of estrogen can attenuate these processes. In 12 girls with the McCune-Albright syndrome (MAS), in which precocious puberty is due to production of estrogen from ovarian cysts, testolactone (40 mg/kg per day) decreased the volume of ovarian cysts, the frequency of menses, and the rates of growth and bone maturation, for periods of 1-4 years. In a 6-month pilot study of 12 children (eight boys; four girls) with congenital adrenal hyperplasia, testolactone, in combination with an antiandrogen (flutamide), a mineralocorticoid (fludrocortisone acetate, Florinef), and a reduced glucocorticoid dose, improved the control of growth and bone maturation compared with conventional therapy. In a 6-year study of 10 boys with familial male precocious puberty, testolactone, in combination with an antiandrogen (spironolactone), decreased rates of growth and bone maturation, and increased predicted adult height. All patients who developed evidence for gonadotropin-dependent puberty were also treated with a GnRH analog. Testolactone had no important adverse effects in any group of patients, although the need for a four-times-daily dosing schedule made compliance difficult for many families. We conclude that suppressing of estrogen with testolactone was effective therapy, and that more potent and specific inhibitors of aromatase could further improve the treatment of these disorders.

Effects of estrogen on nonverbal processing speed and motor function in girls with Turner's syndrome.

The Turner syndrome (TS) phenotype is characterized by a specific neurocognitive profile of normal verbal skills, impaired visual-spatial and/or visual-perceptual abilities, and difficulty with motor function. In the current study, we investigated motor function and nonverbal processing speed in estrogen- and placebo-treated girls (aged 10-12 years) with TS and in age-matched female controls. The goal of this study was to examine whether estrogen replacement therapy would reverse deficits in motor function and in nonverbal processing speed, a measure of the time required to perform certain disparate nonverbal tasks, in adolescent girls with TS. Children received either estrogen (ethinyl estradiol, 12.5-50 ng/kg.day), or placebo for durations of 1-7 yr (mean, 4.0 +/- 2.1 yr) in this randomized, double blind study. Cognitive and motor tasks administered included the Wechsler Intelligence Scale for Children-Revised; nonspatial, repetitive motor tasks (tapping and three tasks from the Paness); and spatially mediated motor tasks [nongrooved pegboard (Lafayette), pursuit rotor, visual-motor integration, and money street map]. Questionnaires administered included the Self-Concept Scale. The major result of this study was the positive estrogen treatment effect on nonverbal processing speed and speeded motor performance in 12-yr-old TS girls. That motor performance would be slower in estrogen-deficient TS females is consistent with previous studies of the influence of estrogen on motor function. Estrogen replacement is thus the most likely explanation for the improved motor speed and nonverbal processing time in the estrogen-treated TS girls compared to that in the placebo-treated TS girls. Whether these findings will influence the psychoeducational outcome or quality of life of females with TS is not yet known.

Visualization of fibrous dysplasia during somatostatin receptor scintigraphy.

Somatostatin receptor scintigraphy was performed on a patient with McCune-Albright syndrome and acromegaly. No evidence of pituitary disease was found, but uptake of (111)In-pentetreotide was noted in areas of fibrous dysplasia. This uptake was not changed after 6 mo of octreotide therapy. The patient's bone disease also remained stable. The possible implications of these findings are discussed.

Absence of growth hormone effects on cognitive function in girls with Turner syndrome.

Turner syndrome (TS) is a genetic disorder characterized by short stature, gonadal dysgenesis, and a particular neurocognitive profile of normally developed language abilities (particularly verbal IQ) and impaired visual-spatial and/or visual-perceptual abilities. We have followed a large sample of girls with Turner syndrome who were enrolled in a long-term, double-blind, placebo-controlled trial of the effects of growth hormone (GH) treatment on final adult height. This study provides a unique opportunity to prospectively evaluate the effects of GH treatment on neurocognitive function in this population of girls with Turner syndrome. The GH- and placebo-treated Turner syndrome subjects were well matched for age, treatment duration, race, karyotype, and socioeconomic status. Treatment (GH or placebo) durations ranged from 1-7 yr. Whether GH deficiency and/or treatment in childhood and adolescence influences cognitive outcome in short children or GH-children is controversial. The major result of this study was the absence of GH treatment effects on cognitive function in girls with Turner syndrome. Our findings are in agreement with most of the previous studies that found no apparent growth hormone treatment effects on cognitive function in growth-hormone deficient children. We conclude that this study does not support a role for growth hormone in influencing childhood brain development in girls with Turner syndrome. Their characteristic nonverbal neurocognitive deficits were not altered with GH treatment into early adolescence.

Regulation of aldosterone in the 7-day-old rat.

Little is known about mineralocorticoid regulation in the neonate. Here, adrenocortical function in 7-day-old Sprague-Dawley rats was studied by measuring the effects of angiotensin II (Ang II) and ACTH on serum aldosterone (ALDO), corticosterone, and cytochrome P-450 ALDO synthetase and 11 beta-hydroxylase messenger RNA (mRNA) levels with and without dexamethasone (DEX) treatment. In the absence of DEX, serum ALDO was unchanged after 5 micrograms/kg, but increased 2- to 12-fold after 50 micrograms/kg, Ang II and 9- to 36-fold after 5 U/kg ACTH. After 4 days of exposure to exogenous ACTH, basal and Ang II-stimulated ALDO were markedly decreased. Basal plasma corticosterone was near or below the assay detection limit and did not change after Ang II, but increased significantly after ACTH administration. After treatment with 200 micrograms/kg DEX, basal serum ALDO fell to below the assay detection limit at 1 h, the responses to 50 micrograms/kg Ang II were attenuated at 1 and 4 h and were undetectable at 18 h. Preincubation of 7-day-old dispersed adrenal glomerulosa cells with 100 nM DEX for 2 h did not decrease basal or stimulated ALDO production. In situ hybridization studies revealed that cytochrome P-450 ALDO synthetase mRNA was confined to the subcapsular zona glomerulosa, whereas cytochrome P-450 11 beta-hydroxylase mRNA was present only in the zona fasciculata-reticularis. DEX caused a time-dependent decrease in P-450 ALDO synthetase mRNA (91 +/- 3%, 77 +/- 6%, 60 +/- 13%, and 38 +/- 19% of the control value at 1, 4, 8, and 16 h, respectively), an effect that was not prevented by ACTH replacement. Only minimal decreases in P-450 11 beta-hydroxylase mRNA levels were observed 18 h after DEX treatment. Hence, the sensitivity of ALDO responses to Ang II in the 7-day-old rat was markedly reduced in vivo, but not in vitro. In addition, DEX markedly reduced ALDO secretion, an effect that was associated with a decrease in cytochrome P-450 ALDO synthetase mRNA.

Self-concept and behavior in adolescent girls with Turner syndrome: potential estrogen effects.

Data on self-concept and behavior were gathered from 31 girls with Turner syndrome (TS) followed longitudinally between the ages of 12 and 16 and from 89 normal control girls recruited from public schools and assessed cross-sectionally. The two groups of girls were similar in age and racial composition. The girls with TS were treated with estrogen replacement therapy in increasing doses between the ages of 12 and 16 (100-400 ng/kg-day ethinyl estradiol). Their self-reported self-esteem and psychological well-being (Piers-Harris Self-Concept Scale) revealed significant improvement over time for most scales as well as the total score (P < 0.001). Parents reported improvement in problem behaviors, as reflected in the Child Behavior Checklist (CBCL) scales: Behavior Total, Externalizing Behavior, Aggressive Behavior, and Social Problems Behavior scales (all P < 0.001). Analysis of covariance comparing normal controls to the TS subjects revealed that at age 12 yr, TS and normal subjects differed significantly for the School Social Competency sub-scale and the Social Problems Behavior subscale (all P < 0.001). Girls with TS resembled the normal controls on all CBCL scales by ages 14-15 yr. Thus, we found improved self-concept both by self- and parental report in estrogen-treated girls with TS followed longitudinally through adolescence. An analogous correlation with age was not seen in the cross-sectional normal control sample. These findings support positive effects of estrogen on psychological well-being in girls with TS and underscores the need to initiate estrogen replacement therapy by ages 12-14 yr in this population.

Growth hormone hypersecretion in a girl with McCune-Albright syndrome: comparison with controls and response to a dose of long-acting somatostatin analog.

GH every 20 min for 24 h, insulin-like growth factor I (IGF-I), IGF-binding protein 3, and estradiol (E2) were measured in a 7.3-yr-old girl with precocious puberty due to McCune-Albright syndrome (MAS) who developed stigmata of early acromegaly and in 9 other MAS patients who had no signs of acromegaly. To determine whether the MAS patients had subtle abnormalities in GH secretion, a computerized pulse analysis program was used to compare the MAS data with those from 27 control girls with central precocious puberty who had a similar rate of bone age advance, E2, and body mass index. We found no differences in mean GH, GH pulse frequency, pulse height, or pulse area between MAS patients and controls except in patient 1, who had an elevated mean +/- SD GH compared with controls (15.4 +/- 2 vs. 4.8 +/- 2.3 micrograms/L; P < 0.01) and an elevated IGF-I (908 micrograms/L) and IGF-binding protein 3 (5.6 mg/L). None of the GH parameters correlated with body mass index, age, bone age, or E2 levels in either group. The serum GH in patient 1 fell to near-undetectable levels from 60-180 min after a 100-micrograms sc dose of long-acting somatostatin, confirming that this form of therapy can be effective in cases of GH hypersecretion due to MAS.

Lipid abnormalities in Turner syndrome.

Turner syndrome is associated with insulin resistance, increased incidence of type II diabetes, and hypertension, all of which are cardiovascular risk factors. The purpose of this study was to evaluate the lipid profile of girls with untreated Turner syndrome, (aged 5 to 14 years; 68% 45,XO) and age-matched, normal girls. A total of 137 girls with Turner syndrome and 70 normal girls had lipid profile measurements, including cholesterol, high-density lipoprotein cholesterol, and triglycerides. Older girls with Turner syndrome (> 11.0 years) had increased cholesterol levels (p < 0.01), compared with control values (190 +/- 38 vs 165 +/- 26 mg/dl). Cholesterol levels were elevated in older subjects with Turner syndrome versus normal subjects, after adjustment for age, karyotype, and body mass index z score effects (p = 0.01). In the subjects with Turner syndrome but not the normal subjects, serum cholesterol values correlated with age, weight, and body mass index z score (p < 0.02). We conclude that adolescent girls with untreated Turner syndrome have significantly increased cholesterol levels, independent of age, body mass index z score, or karyotype, and that these precede any treatment with exogenous estrogen or growth hormone.

Developmental changes in angiotensin II receptor subtypes and AT1 receptor mRNA in rat kidney.

The changes in angiotensin II receptor subtypes, type 1 (AT1) and type 2 (AT2) binding, and AT1 mRNA levels during development were studied in the rat kidney using autoradiographic and in situ hybridization techniques. Autoradiographic analysis of 125I-[Sar1,Ile8]Ang II binding to slide-mounted kidney sections from 2 and 5 day-old rats discerned AT2 binding sites associated with advancing tubules and ampullae of the ureteric bud, and in the metanephric mass in the nephrogenic zone of the cortex. AT1 binding was present in the metanephric mass and immature glomeruli on days 2, 5 and 7 after birth. Differentiating and mature kidneys of 14-day, 21-day and 14-week old adult rats had solely AT1 receptor binding over glomeruli in renal cortex and in the inner stripe of the outer medulla. AT1 mRNA was expressed discretely as early as 2 days of age in the immature glomeruli and in a diffuse radiating pattern in the renal cortex. In the medulla, AT1 receptor mRNA expression appeared discretely on day 7 and reached peak levels on day 21 in the inner stripe of the outer medulla. The data indicate that AT1 receptor mRNA is developmentally regulated in rat kidney and its expression in the cortex precedes that of AT1 receptor ligand binding. The temporal pattern of expression of binding for both receptor subtypes suggests that while AT2 receptors may be involved in cell proliferation and early differentiation of the nephron, AT1 receptors have a dual role, early in nephron differentiation and later in development in renal function.