Lack of association of birth size with polymorphisms of two imprinted genes, IGF2R and GRB10.

Little is known about the determinants of birth size variability among individuals. Maternal and nutritional factors have been studied, but familial clustering suggests genetic factors as well. As a first step in testing this hypothesis, we examined common sequence variants in IGF2R and GRB10, two genes involved in the regulation of growth and subject to parental imprinting. The IGF2R gene was scanned with five polymorphisms spanning the coding and 3'-UTR for possible association with birth size in a set of 97 normal newborns in Greece. In addition, a silent SNP in GRB10 exon 2 was similarly tested as an exploratory first step. Birth weight and length were compared between groups of newborns divided according to which allele they had received from heterozygous parents. No significant differences were found between alleles in either gene, examined either by parental origin or in aggregate. Thus, we found no evidence that IGF2R variants modulate intrauterine growth within the normal range. If such variants exist in GRB10, they are not in linkage disequilibrium with the marker studied.

Genotype-phenotype associations in non-classical steroid 21-hydroxylase deficiency.

OBJECTIVE: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin. DESIGN: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60min 17-hydroxyprogesterone (17-OHP), 45-386nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well. METHODS: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58-151nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. RESULTS: At diagnosis, group B tended to be younger (5. 8+/-3.0 vs 8.1+/-4.3 years, P=0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P=0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62nmol/l, P<0.01). Group B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/-2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P<0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P=0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. CONCLUSIONS: The findings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.

Growth, puberty, and endocrine functions in patients with sporadic or familial neurofibromatosis type 1: a longitudinal study.

OBJECTIVE: This study prospectively evaluates parameters of growth, puberty, and attained adult height in children with sporadic or familial occurrence of neurofibromatosis type 1 (NF-1), followed up longitudinally, to define the most important factors affecting these parameters. PATIENTS AND METHODS: The study was made up of 89 patients (55 boys, 34 girls) with sporadic (n = 45) or familial NF-1 (13 affected fathers and 31 affected mothers). The average age at referral was 8.9 years (range 8.5-15 years), and the average follow-up period was 8.5 years (6-15 years). A total of 28 patients attained adult height at the time of the report. Anthropometric measurements and bone age determinations were performed at 6- to 12-month intervals. As indicated, central nervous system (CNS) imaging was performed on 60 patients. Serum levels of thyroid stimulating hormone, free T4, lutheinizing hormone, follicle stimulating hormone, testosterone or estradiol, cortisol, and prolactin were measured in all patients periodically, and the pituitary growth hormone reserve was assessed in 32 short patients. RESULTS: CNS pathology was found in 23 of the 89 patients. A total of 6 patients required neurosurgery, and 2 patients had cranial irradiation. Of these patients, 3 were receiving recombinant growth hormone and thyroxin replacement therapy and 5 patients with precocious puberty were treated with a gonadotropin-releasing hormone analog. All other patients had normal endocrine tests. Precocious puberty was recorded in 5 patients and was more common among the familial cases. The 5 patients with precocious puberty also had CNS pathology. Short stature (<10th percentile) was observed in 25.5% of the patients during the prepubertal period with a significant gradual reduction of their relative height for age (standard scores) during puberty. Short adult height was noted in 12 (43%) of 28 patients, and only 50% of the 28 patients attained an adult height that was appropriate for their respective target height. Short stature was more common among patients with familial NF-1, particularly if the father was affected, and among those patients with CNS pathology. Parental short stature was observed in 39% of the mothers and in 33% of the fathers (59% and 54% among the affected parents, respectively). Tall stature (>90th percentile) was observed in 4 of 89 patients (4.5%), who all had CNS tumors. A highly significant correlation was found among all adult height-predicting parameters (r =.79), and attained adult height was best correlated with the target height (r =.7; n = 28). CONCLUSIONS: Short adult height is an important characteristic of NF-1 and deserves to be emphasized in the evaluation and follow-up of these patients during childhood. Short adult height is strongly linked with familial background of NF-1, in particular if the affected parent is the father, and is affected adversely by the relatively poor pubertal growth. Despite normal pituitary gland and thyroid function tests in most children and adolescents with NF-1, increased incidence of precocious puberty was observed. As the clinical expression in the second generation is more pronounced, the underlying mechanism seems to be mediated by genetic factors that are yet undefined.

Non-classical 21-hydroxylase deficiency in infancy and childhood: the effect of time of initiation of therapy on puberty and final height.

OBJECTIVE: To review the characteristics of children with non-classical 21-hydroxylase deficiency (NC-21-OHD) diagnosed during infancy and childhood, and to evaluate the relationship of pubertal and bone age maturation at initiation of glucocorticoid therapy with the course of puberty and final height. DESIGN: We retrospectively compared the course of puberty, growth pattern and final height in two groups of patients: group A (two males, six females), hydrocortisone (HC) treatment 7.5-15 mg/m2 per 24 h, initiated > or = 1 year before onset of true puberty and group B (seven females), treatment started with the first signs of true puberty present. PARTICIPANTS: Thirteen girls and two boys with NC-21-OHD diagnosed at age range 0.5-10.6 years were followed-up for 9.0 +/- 3.8 years (mean +/- S.D). Therapy with HC was initiated because of signs of hyperandrogenism, accelerated growth and bone maturation, or true precocious puberty. The HC dose was adjusted according to linear growth and basal plasma androgen levels. RESULTS: Puberty and peak height velocity developed significantly earlier in the girls of group B: gonadarche at 7.9 +/- 1.4 years and peak height velocity at 9.2 +/- 1.4 years vs 10.2 +/- 0.4 years (P = 0.002) and 11.5 +/- 0.7 years (P = 0.006) in group A. Menarche, however, occurred only slightly earlier in group B (12.0 +/- 1.1 vs 12.8 +/- 0.5 years, P = 0.068). All eight children in group A achieved a final height within the range of their mean parental height standard deviation scores (SDS) in comparison with only 1/7 in group B (P = 0.0014). Seven of eight patients who started therapy before a bone age of 9 years achieved a final height within the parental height SDS range, compared with 2/7 who started therapy later (P = 0.041). The final height SDS was significantly better for group A (0.05 +/- 0.19, mean +/- S.E.M.) than group B (-1.63 +/- 0.23, P = 0.0007), even when adjusted for a significant effect of the mean parental height SDS (A. -0.63 +/- 0.28; B, -0.89 +/- 0.31, P = 0.0245, ANCOVA). CONCLUSION: Every child with signs of excess androgen activity or early puberty should be studied for the possibility of NC-21-OHD. Screening programs for populations with a high frequency of the gene for NC-21-OHD would facilitate early diagnosis and treatment. Pubertal stage and bone age at the introduction of therapy dictate height prognosis. Initiation of therapy before puberty with careful follow-up and HC dose adjustment can assure the achievement of genetic adult height.

Prepubertal and pubertal growth, timing and duration of puberty and attained adult height in patients with congenital hypothyroidism (CH) detected by the neonatal screening programme for CH--a longitudinal study.

OBJECTIVE: We have evaluated parameters of growth, the pubertal process and attained adult height in patients with congenital hypothyroidism (CH) of various aetiologies, diagnosed by the neonatal screening programme, and followed up longitudinally. To the best of our knowledge, no such data are available in the published literature. Our aim was to define the most important factors affecting these parameters. PATIENTS AND MEASUREMENTS: Thirty patients with CH (20 females and 10 males) diagnosed by neonatal screening (dysgenetic (n = 15), ectopic thyroid (n = 11), and enzymatic defect (n = 4)), treated with levo-thyroxine (L-T4) since the age of < or = 4 months, and followed up at intervals of 1-6 months for a mean period of 11.4 (range 5-19.6) years were evaluated. Detailed anthropometric measurements were performed by the same trained nurse, and pubertal stages were evaluated according to Tanner's criteria for breast or genitalia and pubic hair. Serum T4 and TSH levels were measured at each clinic visit using commercial kits. Bone age (BA) was determined at 6-12 months intervals using the Greulich & Pyle method. Seventeen patients attained adult height at the time of the report. RESULTS: Mean L-T4 dose of 7.9 (range 5.2-14.0) to 2.4 (range 1.3-3.4) micrograms/kg/day at various ages corrected the serum free T4(f-T4) levels to normal (> 10 pmol/l) in 95% of determinations, and the TSH level was reduced to < 10 mIU/l in 54% of the determinations during the follow-up period. Length at initiation of therapy (mean -0.15, (range -2.5-2.1) SDS), height at onset of puberty (mean -0.4, (range -1.8-1.8) SDS) and adult height (mean 0.2 (range -1.4-2.0) SDS, n = 17) were within the normal range (0.00 +/- 2 SDS). Onset and duration of puberty were normal in both sexes, and total pubertal growth contributed 19.1% (M) and 16.4% (F) to adult height. Peak height velocity (mean 10-6 (range 7.3-15.1) (M) and mean 8.0 (range 6.2-15.5) (F) cm/year) was within the normal range and occurred at the expected BA (14y; M and 12y; F). The attained average adult height was in close proximity to the average target height in both males and females. A significant positive correlation was found between the average L-T4 daily dose administered during the first 6 months of treatment and the attained adult height. CONCLUSIONS: Early detection by neonatal screening and treatment of congenital hypothyroidism enables normal prepubertal and pubertal growth and achievement of normal adult height, following normal puberty. Adult height in congenital hypothyroidism is significantly correlated with parental height and the mean L-T4 daily dose administered over the first 6 months of treatment. A dose of at least 8.5 micrograms/kg/day is recommended during this period. Periodical adjustments of L-T4 daily dose should be guided by clinical observation and serum free T4 levels.

Differential effect of insulin-like growth factor-1 and growth hormone on hypothalamic regulation of growth hormone secretion in the rat.

Pharmacological administration of either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) were reported to inhibit endogenous GH release in humans and in the laboratory animal. We have evaluated the short-term differential mechanisms whereby the two hormones affect hypothalamic regulation of GH secretion. Wistar male rats (90 days old) were injected i.p. with either GH (recombinant GH NIAMDD, Baltimore, MD, USA), rIGF-1 (Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan) or saline. Animals were sacrificed at 15, 30, 60 and 120 minutes following injection. Hypothalami were dissected and extracted immediately and the levels of growth hormone-releasing hormone (GHRH) and somatostatin were determined using specific antisera. Trunk blood was collected for GH and IGF-1 determination by RIA. Administration of IGF-1 or GH markedly decreased hypothalamic somatostatin stores by 77% and 54% respectively, within 15 minutes. Concomitantly, the wide range of GH levels found in the control group was reduced in the IGF-1 treated group suggesting that the pulsatile pattern of GH secretion was suppressed. Growth hormone administration induced an increase in hypothalamic GHRH stores (60% at 120 minutes). During this period serum IGF-1 levels were not altered. It is suggested that short term modulation of hypothalamic neurohormones by GH and IGF-1 is mediated by rapid stimulation of somatostatin release by both hormones, and inhibition of GHRH release is induced only by GH.

Pretreatment with somatostatin analog SMS 201-995 potentiates growth hormone (GH) responsiveness to GH-releasing factor in short children.

Previous studies in children have shown inconsistent, poorly reproducible GH responses to exogenous GH-releasing factor (GRF), with wide individual variability. In the present study, we tested the hypothesis that prior administration of the long-acting somatostatin analog, SMS 201-995 (SMS), will enhance GH responsiveness to a subsequent GRF challenge. Two study protocols were employed in 37 children with short stature [M = 31, F = 6, ages 11.8 +/- 1.6 yr (mean +/- SEM), height -2.25 +/- 0.55 SDS (SD scores)]. In both studies, each subject served as his/her own control. In the first study, which was designed to determine optimal SMS dose and regimen, SMS, in doses ranging from 0.8-2.2 micrograms/kg sc, was randomly administered or omitted at 0800 h after an overnight fast, and a GRF bolus (50 micrograms, iv) was given 4 h later. In the second study, we employed a protocol identical to study 1 except for the use of standard doses of SMS (1 microgram/kg, sc) and GRF (1 microgram/kg, iv) and an additional 1-h delay of the GRF injection. Plasma GH levels were measured every 20 min from 0800 h until 2 h after the GRF injection in both studies. In study 1 (n = 12; M = 10, F = 2), SMS significantly suppressed spontaneous GH secretion (expressed as the mean +/- SEM GH AUC during the 4-h SMS-GRF interval, AUC 1:2.2 +/- 0.4 vs. 6.2 +/- 0.9 micrograms/L.h; P < 0.001), GH responsiveness to GRF (GH AUC during the 2 h after the GRF injection, AUC 2: 41.5 +/- 7.8 vs. 85.0 +/- 13.5 micrograms/L.h; P < 0.001), and the GH peak response (17.4 +/- 3.1 vs. 36.0 +/- 6.2 micrograms/L; P < 0.001), compared to control tests. In contrast, in study 2 (n = 25; M = 21, F = 4), whereas spontaneous GH secretion was still suppressed during the 5-h SMS-GRF interval (AUC 1:3.8 +/- 0.4 vs. 7.4 +/- 1.1 micrograms/L.h; P < 0.001), both the GH peak response (56.7 +/- 5.5 vs. 30.5 +/- 3.0 micrograms/L; P < 0.0001) and the GH AUC (AUC 2: 103.7 +/- 10.3 vs. 77.5 +/- 6.8 micrograms/L.h; P < 0.05) after GRF administration were significantly augmented by pretreatment with SMS, compared to control tests. Taken together, these results indicate that a priming SMS dose of 1 microgram/kg has a significant permissive effect on GH responsiveness to exogenous GRF administered 5 h later.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth in patients with isolated gonadotrophin deficiency.

The growth pattern of 66 patients (50 males, 16 females) with isolated gonadotrophin deficiency (IGnD), who had reached their final height with epiphyseal closure, was evaluated. For the purpose of analysis the males were divided into two groups according to age at referral: group 1 less than 16 years (n = 23) and group 2 greater than or equal to 16 years (n = 27). Sex hormone treatment was initiated at a mean (SD) chronological age of 15.8 (1.3) and 18.6 (1.2) years in groups 1 and 2 in the males and at 15.3 (1.3) years in the females. The duration of treatment (until epiphyseal closure) in the males was 3.9 (1.5) years in group 1 and 2.1 (1.0) years in group 2 and 2.8 (1.3) years in the females. There was no significant difference between the mean final height in groups 1 and 2, but it was significantly higher than the mean parental height (mean height SD score (HtSDS): 0.1 (1.1) v -0.8 (0.9)) and they were significantly correlated. For females the mean HtSDS compared with parental height was 0.4 (1.5) v -0.6 (1.2). It is concluded that the timing of induction of puberty by sex hormones in males and females with IGnD has no significant effect on final height provided that moderate doses are used. Furthermore final height was significantly correlated to mid-parental height.

Relationship between visual acuity and nasal field thresholds in patients with temporal hemianopia.

The area of nasal field found with Goldmann static perimetry and the sum of decibels by Humphrey threshold 30/2 was calculated in normal subjects and in subjects with chiasmatic lesions, temporal field loss, and normal or abnormal visual acuity. There was a significant reduction of the mean of the area of the nasal field by static Goldmann perimetry and of the mean of decibels in the nasal field on Humphrey perimetry in patients with temporal field loss and chiasmatic lesions, as compared with normal controls. There were significant correlations of nasal field depression (Goldmann) and visual acuity and for sums of nasal field decibels (Humphrey) and visual acuity. Thus, a generally depressed nasal field was found in patients with chiasmatic lesions and temporal field loss when accompanied by lowering of visual acuity. This would appear to be the earliest stage of nasal field involvement.

Andrological parameters in human semen of high (greater than or equal to 6 ml) and low (less than or equal to 1 ml) volume.

A study was carried out to evaluate 792 semen of high (greater than or equal to 6 ml) and low (less than or equal to 1 ml) volume and sperm counts ranging from 0.1 to 200 x 10(6) per ml. Particularly emphasized were: motility percentage and grade, percentage viability, morphologically normal sperm and immature cells, and the concentration of fructose in semen (mg/ml). The Duncan multiple range test and the Kruskal-Wallis test with multiple comparison of ranks were used in the statistical analyses. The results show that abnormal semen volume influence neither the basic tendency of andrological parameters to change in accordance with sperm counts of semen nor to correlate with each other. The quality of motility was significantly higher in specimens of high semen volume as compared to those of low semen volume. The concentration of fructose in semen was generally higher in specimens of high volumes than in those of low volumes, including semen devoid of sperm. It was assumed that in general increased semen volume does not affect the quality of other andrological parameters, thus being probably unrelated with fertility potential. The considerably lower values of both motility and viability characterizing the semen of low volume would suggest a lower fertility potential of specimens affected by this type of abnormality.

Persistently low immunoreactive and normally bioactive plasma LH during male puberty.

Low basal and LRH-stimulated (50 mcg/m2 i.v.) levels of plasma immunoreactive (IR) LH were repeatedly found in 8 boys aged 13 to 16 years who had been referred because of delayed onset of puberty (basal IR-LH 0.19 +/- 0.1 and peak 0.48 +/- 0.2 vs. 0.24 +/- 0.09 and 1.71 +/- 0.9 mIU/ml in matched normal controls, respectively). Upon termination of puberty (no more than 3.5 years after referral) IR-LH levels were still low in all 8. Using a rat Leydig cell bioassay system with LER-907 (NPA) as standard, LH bioactivity in these patients was compared with that in 8 matched controls (basal LH was 0.32 +/- 0.33 and 0.11 +/- 0.07, and peak levels 0.8 +/- 0.47 and 1.22 +/- 0.44 mIU/ml respectively). The ratio of basal LH bioactivity to IR-LH was higher in the patients (1.24 +/- 0.95) than in controls (0.47 +/- 0.26, P less than .05) as was that of peak bioactivity (1.89 +/- 1.2 vs. 0.83 +/- 0.35, P less than .05). In the three patients tested during sleep IR-LH levels showed no significant change. Basal plasma testosterone levels were appropriate for pubertal stage (400 +/- 80 ng/dl) and in the four patients tested following prolonged LRH stimulation (500 mcg i.v. over 3 hours) increased to 530 +/- 60 ng/dl. It is concluded that in some boys there may be consistently low plasma levels of IR-LH in association with normal LH bioactivity.

Changes in endogenous insulin secretion during childhood as expressed by plasma and urinary C-peptide.

Basal fasting values of plasma C-peptide (CP), plasma insulin and 24 h urine CP were determined in 224 normal non-obese subjects of both sexes ranging in age from 1 to 20 years. Analysis of the results by age, pubertal rating, sex and bone age (BA) during childhood showed that mean +/- SD plasma CP levels in both sexes rose from 0.07 +/- 0.08 pmol/ml at the age of 1-2 years to 0.21 +/- 0.11 pmol/ml at 8-10 years. Mean +/- SD plasma insulin levels in both sexes rose from 3.2 +/- 4.3 microU/ml at the age of 1-2 years to 5.9 +/- 4.5 microU/ml at 8-10 years. Mean +/- SD urine CP levels rose from 6.5 +/- 2.8 pmol/mg creatinine per 24 h at the age of 2-8 years to 7.7 +/- 3.5 pmol/mg creatinine per 24 h at 8-11 years in both sexes. During puberty, plasma and urine CP and plasma insulin levels rose further to peak at pubertal stage P3, the values in females being higher (CP = 0.32 +/- 0.06 pmol/ml) than those in males (CP = 0.22 +/- 0.06 pmol/ml) (P less than 0.005). Plasma insulin levels in females were 13.2 +/- 6.9 microU/ml and 6.4 +/- 3.1 microU/ml in males (P less than 0.05). Urine CP levels were 14.5 +/- 5.7 pmol/mg creatinine per 24 h and 10.8 +/- 5.4 pmol/mg creatinine per 24 h in females and males respectively (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The evaluation of routine andrological parameters in human serum.

A study was carried out to evaluate the andrological parameters in 540 human semen specimens divided into groups according to sperm counts. The parameters were: motility percentage and grade, percentage of viability and of morphologically normal sperm and immature cells. The Duncan multiple range test and the Kruskal-Wallis test with multiple comparison of ranks were used in the statistical analyses. Of particular interest, among other our findings, were the significant differences obtained by comparing the group with sperm counts up to 5 x 10(6) per ml semen and that with counts ranging from 5.1 to 10 x 10(6) per ml semen. This was true for all parameters with the exception of semen volume. Comparison of the oligozoospermic groups (up to 20 x 10(6)/ml) with those having higher sperm counts also showed significant differences. There was a trend towards improvement of the examined parameters with the increase in sperm density, but with a remarkable heterogeneity particularly within the oligozoospermic groups. In all groups motility, viability and morphological normality of sperm showed a positive correlation with each other. "Normal values" of the parameters studied could be derived from scatterplot charts over the entire range of sperm counts and from the statistical evaluation of the grouped material.

Endocrinological parameters and cell-mediated immunity postoperation for cryptorchidism.

Andrological and endocrinological parameters and cell-mediated immunity (CMI) were assessed in 25 postpubertal males who had undergone repair of unilateral or bilateral cryptorchidism in childhood or early adolescence. Among 20 patients with unilateral cryptorchidism, approximately 30% had decreased sperm density, whereas among 5 bilaterally affected, 1 was azoospermic and 2 oligozoospermic. In most patients the motility and viability values were normal, although the percentage of morphologically pathological sperm was higher than normal. Levels of testosterone, dihydrotestosterone, LH, and prolactin were within normal ranges in all the patients. Levels of FSH were slightly elevated. These findings may suggest a better fertility prognosis of postcryptorchid oligozoospermic patients than in patients with oligozoospermia of other etiology. CMI toward autologous semen revealed a positive reaction in 80% of the bilateral group and in 45% of the unilateral group. This response might be due to the damage of seminiferous tubules of undescended testis causing unmasking and exposure of antigenic determinants.

Episodic hormone secretion during sleep in Kleine-Levin syndrome: evidence for hypothalamic dysfunction.

"Acute" hypothalamic-pituitary function tests including insulin tolerance test, LRH, ACTH and TRH stimulation tests and nocturnal secretory pattern of human growth hormone, 11-OHCS, prolactin, FSH, LH and TSH were studied in a 23-year-old male with Kleine-Levin syndrome during the course of a typical hypersomnic attack. The "acute" tests revealed paradoxical growth-hormone response to TRH stimulation, borderline high basal plasma prolactin levels with normal response to TRH. The hormonal secretory pattern during sleep revealed abnormalities in LH, 11-OHCS and prolactin secretion. These together with the results of the "acute" tests are indicative of an abnormality in the hypothalamic regulation of various pituitary hormones. This observation may indeed be the first laboratory demonstration confirming a long-standing hypothesis that Kleine-Levin syndrome is related to hypothalamic dysfunction.

Diurnal rhythm of plasma beta endorphin, cortisol and growth hormone in schizophrenics as compared to control subjects.

The diurnal variation of plasma beta endorphin was studied in ten schizophrenics, and in age/sex matched control subjects. In the controls beta endorphin was high in the morning (21.0 +/- 3.5 pmol/l) and decreased towards evening. In the schizophrenic group the beta endorphin fluctuated randomly, ranging within 9-40 pmol/l throughout the day. Plasma cortisol showed a normal diurnal pattern in both groups. The mean plasma cortisol levels in the schizophrenics were significantly higher than in the controls throughout the day. The pattern of plasma human growth hormone (hGH) level was similar in both groups at the time tested. It is hypothesized that the instability of beta endorphin secretion may contribute to the pathogenesis of schizophrenia.

Encephalopathy in compensated Hashimoto thyroiditis: a clinical expression of autoimmune cerebral vasculitis.

A young girl with compensated Hashimoto thyroiditis suffered from progressive encephalopathy while euthyroid. Seizures and mental abnormalities responded excellently to corticosteroids only, supporting the view that encephalopathy could be the clinical manifestation of autoimmune cerebral vasculitis.

Neuroendocrine study of a male infant with septo-optic dysplasia.

Septo-optic dysplasia includes abnormalities of the optic nerves and tracts with absence of the septum pellucidum. Most of the recently reported patients were deficient in growth hormone. We describe a male infant with septo-optic dysplasia in whom extensive endocrine evaluation revealed central diabetes insipidus, hypothalamic hypothyroidism and combined (hypothalamic-pituitary) hypoadrenalism, along with normal pituitary growth hormone reserve. This is the first reported case of a patient with septo-optic dysplasia who underwent corticotropin-releasing factor and growth hormone-releasing hormone stimulation.

Intraadrenal steroid concentrations in man: zonal differences and developmental changes.

Adrenal gland samples from 34 individuals 0-68 yr of age were dissected into four layers of equal thickness parallel to the capsule and the zonal boundaries of the cortex, and were analyzed by RIA for their concentrations of 17OH-progesterone, 11-desoxycortisol, cortisol, progesterone, corticosterone, aldosterone, 17OH-pregnenolone, dehydroepiandrosterone, androstenedione, and testosterone, with DNA content to correct for variations in sample size. Intraadrenal steroid concentrations were 10-1000 times higher than reported serum levels, and varied significantly with age, adrenal weight, and cortical thickness. The concentrations of cortisol,11-desoxycortisol, corticosterone, androstenedione, and testosterone increased with age. Levels of 17OH-pregnenolone, dehydroepiandrosterone, and 17OH-progesterone decreased during infancy in parallel with involution of the adrenal, and then rose again in late childhood and puberty. The concentrations of all steroids, except aldosterone, increased significantly from the outer to the inner layers of cortex. Comparisons of product-substrate ratios suggested that changes in adrenal androgen secretion are induced by shifts in the relative activities of key branch-point steroidogenic enzymes, notably 3 beta-hydroxysteroid dehydrogenase-isomerase and 17,20-desmolase. Since intraadrenal steroid concentrations are in the range of the Michaelis-Menten constant (Km) for these enzymes (10(-6) M) and can be shown in vitro at this concentration to influence relative enzyme activities, these data support the hypothesis that zonal and developmental changes in adrenal androgen secretion relative to that of cortisol are induced by changes in the steroidal micro-environment which in turn are imposed by adrenal growth and the centripetal blood flow through the gland.

The pattern of growth in children with constitutional tall stature from birth to age 9 years. A longitudinal study.

A study was made of the longitudinal growth pattern of 29 girls and 36 boys with constitutional tall stature (CTS) from birth to age 9 years. In these children, all of whom had a normal birth length, there was very rapid growth during the first 4 years of life, following which growth velocity dropped to normal and remained parallel to the 50th percentile. In the 49 subjects for whom actual final height was also obtained there was a very good agreement between this and the final height as predicted by Tanner's method from the height at ages 4 and 8 years. Significant differences were found between the mean maternal, paternal and mid-parental height and the tall stature of their offspring, but there was a very good correlation between the individual patients final height and their parental heights. The findings of this study stress the importance of periodical measurements of length and height in all children during the first few years of life so as to have appropriate data on which to base future considerations of possible therapy.