High serum sex hormone-binding globulin (SHBG) and low serum non-SHBG-bound testosterone in boys with idiopathic hypopituitarism: effect of recombinant human growth hormone treatment.

We measured serum sex hormone-binding globulin (SHBG), total testosterone (T), non-SHBG-bound T, albumin-bound T, free T, and SHBG-bound T in 19 prepubertal boys with hypopituitarism. Serum SHBG decreased with age with a slope similar to that in 91 normal prepubertal boys at higher level, and therefore, it reached similar values at a later age. Serum SHBG was significantly higher in hypopituitary prepubertal boys [mean, 123 +/- 12 (+/- SE) nmol/L] than in normal prepubertal boys (76 +/- 4; P less than 0.001) despite the fact that their mean age was also higher (10.0 +/- 4 vs. 7.1 +/- 4.1 yr; P less than 0.001). In 4 boys with isolated hypogonadotropic hypogonadism (Kallman's syndrome), aged 15.6 +/- 1.5 yr, serum SHBG was 21 +/- 14 nmol/L, a value below the 95% confidence limit of the regression line in GH-deficient boys. The affinity constants of association of the SHBG-DHT complex were similar in hypopituitary and normal boys. Eleven of the 19 hypopituitary boys (mean chronological age, 8.3 +/- 2.5 yr; mean bone age, 4.1 +/- 2.1 yr) were treated with recombinant hGH (0.5 U/kg BW.week) for 1 yr. Their mean serum SHBG level before treatment was 154 +/- 14 nmol/L, and it decreased gradually to 106 +/- 5 nmol/L (P less than 0.01) after 12 months of treatment. The tendency toward normalization of serum SHBG during treatment suggested that GH deficiency was responsible for the high serum SHBG levels. Serum SHBG correlated negatively with age in both treated hypopituitary and normal boys, but the slope of the regression line was significantly steeper in treated hypopituitary boys (P less than 0.01). On the other hand, the mean serum non-SHBG-bound T level was 0.10 +/- 0.02 (+/- SE) nmol/L in hypopituitary boys, significantly lower than that in normal boys (0.21 +/- 0.02 nmol/L; P less than 0.02). Since serum total T concentrations were similar in the two groups, the higher serum SHBG concentration resulted in lower serum bioavailable T levels in the hypopituitary boys. These changes might explain the poor response to T treatment reported in GH-deficient patients. The lower serum non-SHBG-bound T concentrations in the GH-deficient boys suggest there may be delayed exposure of central nervous system structures to increased levels of sex hormones, which, in turn, may slow body maturation. This mechanism might play a role in the delay of puberty that occurs in patients with isolated GH deficiency.

Growth in Turner's syndrome: long term treatment with low dose ethinyl estradiol.

The growth response to 100 ng/kg BW X day ethinyl estradiol (2-4 micrograms/day) given for 18 months was studied in a group of nine patients with Turner's syndrome, aged 8.6-13.3 yr. All patients were prepubertal and had elevated gonadotropin levels. Growth velocity increased from 3.09 +/- 1.05 (+/-SD) to 7.09 +/- 1.47 cm/yr in the first 6 months, 6.08 +/- 1.78 cm/yr in the second 6 months, and 4.03 +/- 1.65 cm/yr in the third 6 months. Bone age increased a mean of 0.82 +/- 0.34, 0.89 +/- 0.79, and 0.74 +/- 0.59 yr, respectively, in the three 6-month periods. Predicted height prognosis did not change after any period. All patients had pubertal changes, limited in most to slight breast development. Mean diurnal spontaneous GH secretion did not change during treatment. Plasma somatomedin-C levels were low before treatment, and ethinyl estradiol did not significantly increase somatomedin-C values. Our data confirm the ability of a low dose of ethinyl estradiol to increase growth velocity in girls with Turner's syndrome, although the effect diminished with time, and the excess bone age advancement precluded improvement of predicted height.

Human, bovine, and equine growth hormone antibodies in patients treated with human growth hormone.

The immunological behavior of sera from hypopituitary patients treated with human GH (hGH) has been studied by homologous and heterologous RIAs using 125I-labeled hormones. Along with antibodies against hGH, antibodies exhibiting antibovine and antiequine GH (anti-bGH and anti-eGH, respectively) activities were also found. Displacement experiments showed that hGH was an effective competitor of 125 I-labeled hGH, whereas bGH and eGH were quite inefficient. Conversely, when the tracer was 125I-labeled bGH, both bGH and eGH were good displacers, while the human hormone was poor. The values of the affinity constants of the various antibodies found in human sera were similar to each other and to those found after immunization of rabbits. These results suggest that the antibodies against bGH and eGH belong to a population separate from those directed against the human hormone. The mechanism by which hGH can express determinants of other animal growth hormones is obscure, although the high degree of conservation of structure in these molecules during evolution must be involved.

Phenotypic heterogeneity in familial isolated growth hormone deficiency type I-A.

We studied an Argentinian family of Spanish ancestry in which the parents are of normal height and three of their four children have isolated GH deficiency type I-A. Restriction endonuclease analysis of DNA isolated from leukocytes was done using 32P-labeled human GH (hGH) cDNA sequences as a probe. The three siblings were homozygous, while their parents and the remaining sibling were heterozygous for a deletion of about 7.5 kilobases DNA, which included the normal hGH gene. The phenotype of the affected subjects differed in several respects. There was variation between the homozygotes in birth length and height before hGH treatment and growth responses during long term hGH treatment. Furthermore, heterozygotes in this family had normal height despite their diminished hGH responses to provocative tests.

The codon 213 of the 11beta-hydroxysteroid dehydrogenase type 2 gene is a hot spot for mutations in apparent mineralocorticoid excess.

In the kidney, the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11betaHSD2) inactivates glucocorticoids to their inactive ketoforms and thus prevents endogenous glucocorticoids from occupying the nonselective mineralocorticoid receptor in epithelial tissues. Several mutations have been described in the 11betaHSD2 gene in the congenital syndrome of apparent mineralocorticoid excess. These mutations generate partially or completely inactive 11betaHSD2 enzymes. In the present work, we describe an already known mutation in a new patient affected by apparent mineralocorticoid excess, which results in an arginine-to-cysteine mutation (R213C) in the 11betaHSD2 enzyme. This mutation has been found in two other independent families. In vitro expression studies of this mutant provide evidence that the mutant protein is normally expressed, but its activity is abolished. The CGC-to-TGC (C-toT) transition at codon 213 can be considered a typical CpG-consequence mutation. The present finding suggests that the codon R213 of 11betaHSD2 is a hot spot for mutations in this gene, as shown by the occurrence of an R213C point-mutation in several families unrelated to each other.

Estrogen priming effect on growth hormone (GH) provocative test: a useful tool for the diagnosis of GH deficiency.

We have studied the effect of estradiol (E2) on the GH-insulin-like growth factor (GH-IGF) axis in 15 prepubertal GH deficiency (GHD) children and 44 prepubertal or early pubertal children with idiopathic short stature (SS). All of them received a daily dose of micronized E2 (1 or 2 mg) or placebo, for 3 days, before a sequential arginine-clonidine test. In SS children, GH maximal responses were 17.8+/-10.9 on placebo and 27.9+/-14.5 microg/L on estrogen (P < 0.0001). The lower 95% confidence limits for GH maximal response changed from 3.7 microg/L (without E2) to 8.3 microg/L (on E2). In GHD children, no significant stimulatory effect of estrogen on GH levels was observed. After placebo, a cut-off limit of 3.7 microg/L (the lower 95% confidence interval limit) resulted in 73% sensitivity, 95% specificity, and an overall 90% diagnostic efficiency. After E2, a cut-off limit of 8.3 microg/L resulted in a sensitivity of 87%, a specificity of 98%, and a diagnostic efficiency of 95%. After placebo, 68% of SS showed normal IGF-I levels, and the mean did not change on E2 (13.7+/-6.3 vs. 14.3+/-6.8 nmol/L, not significant). In 93% of SS, IGF binding protein (IGFBP)-3 levels were normal during placebo. On E2, mean IGFBP-3 did not change (2.63+/-0.70 vs. 2.70+/-0.70 mg/L, not significant). In 14 of 15 GHD patients, IGF-I values were below normal on placebo, and the mean of the group did not change after E2. During placebo, 13 of 15 GHD children presented low IGFBP-3 values. During E2, there was a small significant increase in IGFBP-3 values (1.06+/-0.58 vs. 1.20+/-0.69 mg/L, P < 0.02). The highest diagnostic efficiencies for IGF-I and IGFBP-3 were observed during placebo (75% and 91%, respectively). We conclude that GH stimulation tests after E2 priming had the highest diagnostic efficiency. Our findings suggest that the effect of estrogen priming on GH stimulated levels, by reducing the number of false nonresponders, might be useful to better discriminate between normal and abnormal GH status in SS children.

The physician's assistant as resident on surgical service. An example of creative problem solving in surgical manpower.

A residency program for physician assistants (PAs) on a surgical service was undertaken to develop health professionals who could serve in a capacity similar to that of junior surgical residents helping to deliver preoperative and postoperative care under the supervision of surgeons and assisting in operations. As the number of approved surgical residencies and the number of individuals available for residency has decreased, a manpower void is occurring in some institutions in providing in-house services to surgical patients. The use of medical or family practice residents or full-time in-house surgeons is not totally satisfactory. A PA with special training in surgical case management and operative assisting meets many needs previously provided by surgical residents. The surgical PA is, indeed, a surgeon extender and seems, from our three-year experience, to be a good solution to this problem of surgical care in community hospitals. This program also provides an educational mission for the institution and the surgical staff.

A novel E153X point mutation in the androgen receptor gene in a patient with complete androgen insensitivity syndrome.

AIM: To study a 46, XY newborn patient with a phenotype suggestive of an androgen insensitivity syndrome to confirm an anomaly in the AR gene. METHODS: Genomic DNA from leukocytes was isolated in order to analyze SRY gene by PCR and sequencing of the eight exons of AR gene. Isolation of human Leydig cell mesenchymal precursors from the testis was performed in order to study testosterone production and response to hCG stimulation in culture. RESULTS: Surgical exploration disclosed two testes, no Wolffian structures and important Müllerian derivatives. The SRY gene was present in peripheral blood leukocytes. Sequencing of the AR gene evidenced a previously unreported G to T transversion in exon 1 that changed the normal glutamine 153 codon to a stop codon. Interstitial cell cultures produced sizable amounts of testosterone and were responsive to hCG stimulation. CONCLUSION: This E153X nonsense point mutation has not been described previously in cases of AIS, and could lead to the synthesis of a short truncated (153 vs 919 residues) non functional AR probably responsible for the phenotype of complete androgen insensitivity syndrome (CAIS).

Reproducibility and comparison of growth hormone secretion tests.

To assess the degree of reproducibility of spontaneous GH secretion and pharmacological tests we studied 15 prepubertal children with short stature and abnormal growth rate. In all children, spontaneous overnight GH secretion was measured followed by a clonidine test in 8 children and an arginine test in the remaining 7. The same protocol was repeated a week later. Intra-individual variability of GH secretion in both physiological and pharmacological tests was expressed as the coefficient of variation (CV%). No significant difference was found between the first and second value of parameters of spontaneous GH secretion. Maximum spontaneous GH peak (MS) and mean 12-h GH concentration (MGH) correlated significantly (r = 0.78, p < 0.001). Mean CV% of all parameters of repeated GH profiles (around 30%) were lower than those of provocative tests (around 70%) (p < 0.05). No significant difference was found between CV% of clonidine and arginine tests. There was no correlation between MGH or MS and GH response to provocative test in the same child. We found a significant correlation between the log transformed maximum provocative GH response to the arginine test and the length of the time interval (in min) from the end of the last GH peak in the previous profile to the time zero of the provocative test (r = 0.60, p < 0.05). This relationship was not found for the clonidine test. We conclude that spontaneous GH secretion in children with short stature is more reproducible than stimulated GH response with a week's difference. Perhaps the higher variability of provocative GH secretion may be related to the state of the endogenous hypothalamic rhythm of both GHRH and somatostatin release at the time of the test.

Psychosocial outcome in growth hormone deficient patients diagnosed during childhood.

Social disabilities have been described in GHD patients. The aim of this study was to evaluate the social outcome of a group of adult hypopituitary patients diagnosed and treated during childhood. Seventy patients were interviewed at a mean age of 25.6 years (range 18-50 yr). They answered a semistructured questionnaire and the Beck Depression Inventory test. Patients were compared for academic achievement, marital status and employment with the nearest age sibling. We found high levels of school repeaters, school was often not completed, and around 50% were overprotected by teachers and teased by peers. 32% were unemployed, while 58% of those employed work with their families. 80% still live with their parents; only 16% are married and 9% have children. 44% had no dating experience and 52% had never had sexual intercourse. Depression was common, especially in hypogonadic subjects. Juvenilization was the most common complaint. We did not found differences in maximal educational achievements and levels of employment between patients and siblings, but significantly more married siblings were found. Depression, social isolation and dependent life style were found in GHD patients. Appropriate medical and psychological counseling should be included for patients and their families as part of treatment.

Thyroid dysfunction and high thyroid stimulating hormone levels in children with Down's syndrome.

UNLABELLED: In order to delineate the spectrum of thyroid abnormalities in children with Down's syndrome (DS), first visit height data (SDS) and serum TSH, T4 and antiperoxidase antibodies concentrations were retrospectively evaluated in 137 children (71 girls) with DS (0.04-16 years). RESULTS: Congenital hypothyroidism was detected in 2.9% of patients. Thyroid disease occurred in 9%: four hyperthyroidism and eight hypothyroidism. Overt thyroid disease was always related to thyroid autoimmunity. The remaining 121 patients had normal T4 levels but increased mean TSH compared with controls (4.7 +/- 2.8 vs 2.3 +/- 1.3 mU/l). According to TSH levels, they were divided into two groups: G1 (n = 68) with normal TSH (<5 mU/l), and G2 (n = 53) with high TSH (> 5 mU/l). T4 levels were significantly lower in G2 (p < 0.01 vs G1 and controls). Height SDS was not different. CONCLUSIONS: Thyroid disorders are frequent in children with DS. Subtle thyroid abnormalities found in patients with DS with no evidence of clinical dysfunction need further investigation to demonstrate whether there is a need for therapeutic intervention.

Final height in long-term primary hypothyroid children.

OBJECTIVE: We studied retrospectively the statural growth and bone maturation of 32 children with primary hypothyroidism in order to relate their final heights to their chronological ages, height deficits and bone ages at the beginning of treatment. Patients were grouped according to age when treatment was started: Group 1 (G1) (n = 17): (15 girls, 1 boy) 3.09 +/- 0.8 yr; Group 2 (G2) (n = 9): (7 girls, 2 boys) 9.1 +/- 1.2 yr, and Group 3 (G3) (n = 6): (5 girls, 1 boy) 13.58 +/- 1.13 yr. At diagnosis G1 and G2 were prepubertal and G3 children were in puberty. In 10 patients of G1, 7 of G2 and 6 (all) of G3 final height was compared with target height. RESULTS: (SDS) Initial height: G1: -3.74 +/- 1.2; G2: -3.94 +/- 1.32; G3 -3.65 +/- 1. Height at onset of puberty: G1: -1.06 +/- 1.1; G2: -2.5 +/- 1.4. Height menarche stage 5: G1: -0.63 +/- 1.1; G2: -1.76 +/- 1.2; G3: -2.6 +/- 1.7. Final height: (whole group) G1: -0.85 +/- 0.91; G2: -1.6 +/- 1.3; G3: -2 +/- 1.5. Final height G1 (n = 10): -1.05 +/- 0.89; G2 (n = 7) 1.2 +/- 1. Target height G1 (n = 10): -1.22 +/- 0.78; G2 (n = 7): -0.8 +/- 1.2; G3 (n = 6): -1.07 +/- 1.5. Initial bone age: G1: -4.9 +/- 0.85; G2: -7.2 +/- 2.6; G3: -4.5 +/- 1.9. Bone age (onset of puberty) G1: -0.26 +/- 1.74; G2: -2 +/- 1.7; Bone age (menarche) G1: 0.09 +/- 0.6; G2: -0.5 +/- 0.6; G3: -0.76 +/- 0.82. CONCLUSION: G1 and G2, prepubertal at diagnosis, reached a normal adult height with respect to target height; G3 did not, the difference being statistically significant (p < 0.04). Puberty plays a decisive role in the incomplete catch-up growth of longstanding hypothyroid patients.

The role of topical treatment as a determinant of infection in outpatient burns.

Up to 95% of all burned patients are treated as outpatients. While uniform guidelines exist to evaluate the severity of an outpatient's burn, treatment forms vary greatly. Furthermore, the relative merits of one treatment modality over another have not been demonstrated. This study reviews 262 patients with uncomplicated, thermal partial-thickness burns. All of these patients were treated with either a petrolatum fine-mesh gauze (FMG = 102), a topical penetrating antibacterial agent (TPA = 58), or a topical nonpenetrating antibacterial agent (TNA = 102). The size of the injury along with its location and etiology, the age of the patient, the time from injury to treatment, and comorbid factors were comparable among the major treatment groups. On follow-up, a wound was classified as infected if it exhibited erythema, tenderness, increased warmth, and edema (cellulitis). Infection rates were 2.0% (2/102) in the FMG group, 5.2% (3/58) in the TPA group, and 2.0% (2/102) in the TNA group. The differences among the rates did not reach statistical significance (P = 0.41). Given the cost of treatment, frequency of dressing changes and overall patient comfort, we advocate FMG as the optimal method for the care of uncomplicated partial-thickness outpatient burns.

Determining the current roles of physical and occupational therapists in burn care.

The team approach has enjoyed great success in the care of patients with burns, and it has been shown to decrease morbidity and mortality in these cases. Although the concept of the team approach is well-defined, the delineation of roles within this approach remains unclear. This study was designed to better explain the roles of physical therapists (PTs) and occupational therapists (OTs) in burn care. With the use of a questionnaire, PT and OT responsibilities were reviewed. The results showed that OTs perform the majority of activities of daily living training, PTs perform the majority of functional mobility training, both professions are involved in scar management, and neither profession has significant responsibility for care of the burn wound itself. Role delineation occurs to help avoid role confusion and the duplication of services. The title burn therapist offers an example of unclear role definition when a physical therapy assistant uses that title to identify himself or herself. Communication is critical to define these roles within individual burn centers.

The burn camp experience: variables that influence the enhancement of self-esteem.

Since 1982, there have been summer camps for children and adolescent burn survivors. Although the primary focus of camp is to have "fun," the principal goal is psychosocial readjustment through peer interactions and the resulting enhancement of self-esteem (SE). This study was initiated to test the hypothesis that the burn camp experience enhances the SE of campers. Forty-three campers at the Connecticut Burns Care Foundation Summer Camp were invited to participate in this study with the Rosenberg Self-Esteem Scale. The age range was 8 to 18 years (mean 12 years). The extent of previous burn injury ranged from 10% to 98% total body surface area (mean 40%). The interval between hospital discharge and camp experience was 4 to 144 months (mean 54 months). Thirty-seven percent of the children demonstrated an increase in SE to varying degrees, whereas 30% showed no change, and 3% exhibited a decrease in SE. This study failed to support the working hypothesis.

[Magnetic resonance imaging in central diabetes insipidus in children and adolescents. findings at diagnosis and during follow-up]. / Resonancia magnética en niños y adolescentes con diabetes insípida central: hallazgos al diagnóstico y durante su seguimiento.

AIM: The absence of the hyperintense signal of the posterior pituitary in magnetic resonance imaging (MRI) is considered by some authors to be evidence of neurohypophyseal dysfunction. To evaluate the utility of MRI as a complementary diagnostic aid in patients with central diabetes insipidus (CDI), we studied the MR images of pediatric patients at diagnosis and during follow-up. METHODS: MR images from 14 patients (4 females, 10 males; mean age 8.5 years) who were referred for polyuria and polydipsia and whose diagnosis was central diabetes insipidus (CDI) were analyzed. Mean time of evolution from onset of polyuria until the first MRI was 1.5 years. In 11 patients more than one MR image was obtained during follow-up. Mean time of follow-up was 2.8 years. RESULTS: In 10 patients CDI was idiopathic, in 3 it was secondary to a hypothalamic tumor and in 1 it was secondary to histiocytosis. In one patient with idiopathic CDI, the hyperintense signal was present at diagnosis but disappeared during the following 15 months. Four of the patients with idiopathic CDI developed thickening of the pituitary stalk, some at their diagnosis and others during follow-up. Of the three patients in whom CDI was secondary to a germinoma, the hyperintense signal was absent in two of them, while in one the signal was ectopic and associated with a thickened pituitary stalk. In the patient with histiocytosis, the hyperintense signal was absent at diagnosis. CONCLUSIONS: 1. In most of the patients with CDI the hyperintense signal of the posterior pituitary was absent at diagnosis; however in one patient this signal disappeared during follow-up and consequently its presence does not rule out a diagnosis of CDI. 2. Although a thickened pituitary stalk could reflect only a non-specific, transient inflammatory process, its presence makes ruling out tumoral or infiltrative disease obligatory.