Undetectable levels of tumor necrosis factor-alpha, nitric oxide and inadequate expression of inducible nitric oxide synthase in congenital hypothyroidism.

OBJECTIVE: To analyse the production of TNF-alpha and NO in euthyroid and hypothyroid newborns. PATIENTS: A cross-sectional study was conducted involving 10 newborns diagnosed with primary congenital hypothyroidism (CH; group A) and 10 euthyroid children (group B). RESULTS: There were undetectable plasma levels of TNF-alpha and NO in the hypothyroid children, however plasma levels of TNF-alpha (5.5 0.5 pg/ml) and NO (5.6 1.7 microM) were detected at normal levels in all euthyroid children. Moreover, expression of iNOS mRNA in PBMC, determined by RT-PCR, was negative in both groups of infants. CONCLUSION: TNF-alpha and NO production are both impaired in hypothyroid newborns. We report for the first time evidence of undetectable levels of TNF-alpha and NO in infants with CH.

Influence of growth hormone on accretion of bone mass.

Growth hormone (GH) exerts important influences on bone metabolism during lifespan. During childhood, GH is a major determinant of acquisition of bone mass and in adult life, GH partly determines the rate of bone remodelling and therefore influences maintenance of bone mineral density (BMD). Insights into the importance of GH in these respects may be obtained by studies of BMD and indices of bone remodelling in GH deficiency (GHD) of adult-onset and childhood-onset. Adult-onset GHD, usually accompanied by other features of hypopituitarism, may be associated with osteopenia and an increased fracture risk. Postulated mechanisms include GHD and gonadal steroid deficiency of unknown duration; glucocorticoid and thyroxine replacement do not appear to exert a major role. GH replacement in adult-onset GHD results in an early increment in indices of bone remodelling which persists for up to 5 years; BMD increases by 0.5-1.0 SD in males and stabilizes in females over this time period. In adolescents with GHD who traditionally discontinue GH at completion of linear growth, BMD is substantially lower than peak bone mass for a young adult population. Studies addressing the effects of continuation of GH after achievement of final height are currently underway and will provide insights into the possible need to continue GH into adult life. Such studies may confirm a role for GH in promoting continued accrual of bone mass and thereby demonstrate that cessation of GH at achievement of final height, by limiting peak bone mass, may predispose to clinically significant osteoporosis in later life. In addition to the potential importance of GH for achievement of peak bone mass, there may be a superimposed accelerated loss of BMD with advancing age similar to the situation observed in adult-onset GHD. To date, this has been difficult to assess in adult GHD of childhood-onset because the relative contributions of low peak bone mass and increased loss of bone in later life could not be distinguished.

Hiperplasia suprarrenal congénita por defecto de la 21-Hidroxilasa / Congenital adrenal hyperplasia due to 21-hydroxylase deficiency

La disponibilidad de los estudios moleculares ha permitido en los últimos años abordar el estudio de la hiperplasia suprarrenal congénita (HSC) con una mayor especificidad y desde una perspectiva más amplia de diagnóstico. Actualmente, podemos plantearnos, no sólo el diagnóstico de pacientes, sino también un diagnóstico presintomático, prenatal o neonatal tras cribado bioquímico, al igual que un diagnóstico más veraz de portadores. Todo ello permite una prevención y un mejor planteamiento del control y seguimiento de estos pacientes, lo que es de gran relevancia, ya que en esta enfermedad es posible realizar un tratamiento prenatal que previene la virilización de las niñas afectadas. La HSC se debe en la gran mayoría de los casos (90-95 por ciento) a la deficiencia de esteroide 21-hidroxilasa y, como causa secundaria y ya muy distanciada, a la deficiencia de 11-beta-hidroxilasa, dando cuenta ambas del 99 por ciento de los casos. Este artículo se centra en estos déficit mencionados y trata de aportar nuestra experiencia concreta en lo que se refiere a la utilidad del estudio molecular en la HSC.Se presentan los datos obtenidos en el estudio de un amplio número de familias española -más de 300-, incluyendo las distintas formas clínicas de la deficiencia: pier-de-sal, virilizante simple, no clásica o atenuada y críptica, analizándose la relación genotipo/fenotipo. El estudio se centra en formas pediátricas de la deficiencia y, de manera especial, en aspectos moleculares, que ocasionalmente se relacionan con pará-metros bioquímicos, pero en ningún caso es objetivo de este estudio la clínica desarrolla-da por estos pacientes, ya que otros autores clínicos podrán aportar su experiencia de forma más cualificada. En relación con la terapéutica, se refieren aquellos aspectos que mantienen una relación con el estudio molecular, mínimamente la terapia génica y celular, ya que su desarrollo en este campo es prácticamente nulo, y de una forma más extensa, nuestra experiencia en el diagnóstico prenatal. El defecto de la enzima 21-hidroxilasa en la esteroidogénesis suprarrenal es la causa más frecuente de genitales ambiguos en la recién nacida y de virilización precoz en el varón. En la mayoría de las formas graves el defecto de la 21-hidroxilasa también produce una disminución en la síntesis de mineral corticoides, lo que conlleva la aparición de crisis de pérdida salina, situación potencialmente letal. El tratamiento de esta enfermedad es multidisciplinario y se basa en sustituir la insuficiente producción de cortisol y aldosterona, evitando los efectos secundarios inherentes al sobretratamiento. La reconstrucción quirúrgica precoz de la niña virilizada y el apoyo psicológico de los pacientes y de sus familias son aspectos importantes del tratamiento. El diagnóstico precoz mediante programas de cribado neonatal hace posible instaurar la terapia adecuada y evitar los episodios de pérdida salina. El estudio molecular establece la alteración génica del paciente y su familia, permite realizar un consejo génetico y, en su caso, el diagnóstico y tratamiento prenatales que evitan la virilización de los genitales del feto femenino afectado (AU)

The influence of gender on the short and long-term effects of growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults: a 5-year study.

OBJECTIVES: The objectives of this study were to investigate the effects of GH replacement therapy in hypopituitary adults with growth hormone deficiency (GHD) on activation of bone remodelling during dose titration and on BMD over a median of 58 months of continuous therapy. STUDY DESIGN: Open label study in adult patients with GHD. rhGH was commenced at dose of 0.8 IU subcutaneously daily (0.4 IU if hypertensive or glucose tolerance impaired) with subsequent dose titration based on 2 weekly measurement of serum IGF-I until levels reached the target range (between the median and upper end of the age related reference range). In patients previously commenced on GH using weight based regimens the dose of GH was adjusted during clinical follow-up in order to maintain serum IGF-I in the target range. PATIENTS: Initial effects of GH on bone remodelling during dose titration were studied in 17 patients (8F). Long-term effects of GH were determined in a separate group of 13 GHD adults (6F) over a median period of 58 months (range 44-72). MEASUREMENTS: Osteoblastic activity was estimated by measuring serum bone specific alkaline phosphatase (S-BAP). BMD was determined at both lumbar spine (L2-L4) and femoral neck by dual energy X-ray absorptiometry (DEXA). RESULTS: During dose titration a significant increment in S-BAP was observed by 10 weeks in females but occurred later in males (12-26 weeks). In the long term treatment group there was a significant increment in S-BAP compared to baseline (P = 0.013) after 6 months GH treatment. After long-term GH treatment (median 58 months) S-BAP levels decreased and were no longer statistically significantly different from baseline at the end of the study period. A similar response was observed in male and female patients. There were no significant differences in baseline BMD between male and female patients at either lumbar spine or femoral neck in the long term treatment group. No significant changes were observed in BMD after 6 months GH treatment in either lumbar spine or femoral neck but BMD increased over the remainder of the study at both sites (P = 0.023 and P = 0.03 respectively). When analysed by gender male patients showed a clear positive change in BMD after longer-term replacement in both lumbar spine and femoral neck (P = 0.01 and P = 0.02 respectively) but female patients showed no significant changes. Qualitatively similar results were observed when analysing changes in BMD expressed as Z scores. CONCLUSION: This study demonstrates an earlier onset of GH activation of bone remodelling as reflected by S-BAP in females compared to males and confirms that long-term GH treatment in hypopituitary adults with GH deficiency increases or preserves BMD both at lumbar spine and femoral neck. However male patients seem to derive the greater benefits in BMD from long-term GH replacement; in females BMD appears simply to be stabilized rather than increased. This constitutes a genuine gender difference in susceptibility given that serum IGF-I was in the upper part of the reference range in all subjects.

Effects of growth hormone replacement on physical performance and body composition in GH deficient adults.

OBJECTIVES: Adults with GH deficiency complain frequently of low energy levels resulting in a low perceived quality of life. Body composition is altered, with increased fat mass and decreased lean body mass, and muscle strength is reduced. The aims of this study were to determine the effects of GH replacement on physical performance and body composition in GH deficient (GHD) adults. STUDY DESIGN: The study consisted of a 6-month randomised, double-blind, placebo controlled study of the administration of GH (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17F), mean age 39.8 years (range 21.1-59.9), on conventional replacement therapy as required. METHODS: Maximum aerobic capacity was measured using an incremental walking test to volitional exhaustion on a motorized treadmill. Quadriceps muscle strength was assessed by measuring maximum voluntary contractions and body composition by dual energy X-ray absorptiometry (DEXA). RESULTS: There were no statistically significant changes in quadriceps muscle strength between the GH and placebo groups. In both groups, there was a significant increase in quadriceps muscle strength compared to baseline during the double-blind period (GH group: P = 0.016; placebo group: P = 0.048). Compared to baseline, muscle strength was further improved in the GH treatment group after 12 months of treatment (P = 0.007). No further improvement was noted in the placebo group after 6 months on open GH treatment. In the placebo group, maximum aerobic capacity decreased during the placebo period (P = 0.017). No significant change was observed in the GH group. During open GH treatment the previously placebo treated group had a significant increase of maximum aerobic capacity (P < 0.049) whereas no significant improvement could be seen in the GH group. In the GH group there was a significant increase in lean body mass (P = 0.001) and a significant decrease in fat mass (P < 0.001). No statistically significant changes were noted in the placebo group: the differences in these changes between treatment groups were statistically significant (lean body mass: P = 0.009; fat mass: P < 0.001). The changes in body composition in the GH group during the 6 month placebo-controlled period were maintained during continued open treatment. Similar changes in body composition to those observed in the GH group during the 6 month placebo-controlled period were also seen in the placebo group once the patients received GH treatment. CONCLUSIONS: Our data show that GH replacement in GH deficient adults is associated with favourable changes in body composition, which could be important in the long term health outcome and physical activity of GH deficient patients. Our data support the concept that GH therapy alone, in the absence of some form of exercise programme, may increase the amount of lean tissue but not the quality or functional capacity of this tissue and it may be that training, in addition to GH therapy, may be necessary to significantly increase physical performance in these patients. We suggest that future trials with GH therapy and general approaches to the treatment of GH deficiency should include a planned activity programme as an approach to health improvement in these patients.

Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels.

Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.

Serum collagen crosslinks as markers of bone turn-over during GH replacement therapy in growth hormone deficient adults.

OBJECTIVES: Bone metabolism is an important target for GH replacement therapy. However, in adults, treatment periods exceeding 12 months are required for a positive effect of GH on bone mineral density. Thus, to detect an early effect of GH on bone, markers of bone turn-over are important. Pyridinoline (PYR) and deoxypyridinoline (DPYR) are well-defined sensitive markers of bone resorption, but to date only urinary assays have been available. We report the use of a novel assay to measure changes in serum PYR and DPYR in GH deficient (GHD) adults during GH replacement therapy. STUDY DESIGN: The study consisted of a 6-month randomized, double-blind, placebo-controlled study of the administration of GH (Genotropin) (0.25 IU/Kg/week (0.125 IU/kg/week for the first four weeks)) followed by a 6-month open phase of GH therapy. PATIENTS: Thirty-five GHD adults (17 women; mean age 39.8 years; range 21.1-59.9) on conventional hormone replacement therapy as required, were studied. MEASUREMENTS: Bone formation was analysed using serum bone alkaline phosphatase (BAP) and serum osteocalcin (OC). Bone resorption was analysed using serum pyridinoline (PYR) and serum deoxypyridinoline (DPYR). Bone mineral density (BMD) was determined by dual energy X-ray absorptiometry (DEXA). RESULTS: After 6 months placebo treatment there were no significant changes in any of the bone markers analysed, nor in BMD. In the active arm of the study there was a significant increase in serum OC, BAP, PYR and DPYR (P = 0.03, P = 0.004, P = 0.003 and P = 0.01, respectively), remaining significantly elevated over their baseline levels for the subsequent 6 months of treatment (P = 0.04, P = 0.009, P = 0.003 and P = 0.04, respectively). No changes were observed in BMD in any of the groups after 6 months GH treatment. In the active arm of the study, after 12 months GH treatment there was a significant increase in BMD at both the lumbar spine and femoral neck (P = 0.01 for both sites). CONCLUSIONS: In summary, the present study confirms that administration of GH treatment to GHD adult patients significantly activates bone remodelling, with the effect of GH both in bone formation and bone resorption markers being maximal after 6 months of treatment. The serum assay for PYR and DPYR has a number of practical and theoretical advantages over the urine assay and gave similar results to those previously reported for the urine assay.

Reduction in circulating IGF-I and hepatic IGF-I mRNA levels after caecal ligation and puncture are associated with differential regulation of hepatic IGF-binding protein-1, -2 and -3 mRNA levels.

Sepsis is characterized by a severe shift in metabolism, characterized by low IGF-I levels. We have studied the influence of caecal ligation and puncture (CLP) on the levels of circulating IGF-I and hepatic IGF-I and IGF-binding protein (IGFBP)-1, -2 and -3 mRNA in adult male Wistar rats (n = 12) and compared it with sham-operated rats (n = 6). In order to exclude anorexia-induced changes we also studied animals pair-fed to both groups. IGF-I levels were measured by RIA. Steady-state hepatic IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 mRNA levels were measured by Northern blot analysis using specific rat cDNA probes. Food intake averaged 13.0 +/- 2.0 g/day in the sham-operated rats fed ad libitum during the study period, with a sharp decline in food intake in the CLP animals (2.3 +/- 1.3 g/day). After CLP, there was a significant reduction in circulating IGF-I levels (467.2 +/- 50.9 micrograms/l) compared with sham-operated animals (924.0 +/- 75.3 micrograms/l; P = 0.04) or those pair-fed to the CLP rats (612.5 +/- 52.9 micrograms/l; P = 0.04). Total hepatic IGF-I mRNA levels were significantly reduced (2.57 +/- 0.05 densitometric units (DU) after CLP compared with the sham-operated group (2.71 +/- 0.04); P = 0.04), or their pair-fed controls (2.75 +/- 0.08 DU; P < 0.05). Hepatic IGFBP-3 mRNA levels were lower after CLP (0.37 +/- 0.04 DU) than in the sham-operated animals (0.66 +/- 0.09 DU; P = 0.04) or their pair-fed controls (0.61 +/- 0.05 DU; P = 0.04). On the other hand, hepatic IGFBP-2 mRNA levels were increased after CLP (0.91 +/- 0.11 DU) compared with sham-operated animals (0.28 +/- 0.06 DU; P = 0.01) or with their pair-fed controls (0.22 +/- 0.02; P = 0.01), as were hepatic IGFBP-1 mRNA levels (CLP animals 0.95 +/- 0.11 DU; sham-operated 0.30 +/- 0.04 DU, P = 0.01; pair-fed 0.30 +/- 0.02 DU, P = 0.01). No significant difference between sham-operated animals and their pair-fed controls was observed in circulating IGF-I levels (888.0 +/- 109.3 micrograms/l; P = not significant (N.S.)), hepatic mRNA levels for IGF-I (2.72 +/- 0.06 DU; P = N.S), IGFBP-3 (0.71 +/- 0.07 DU; P = N.S.), IGFBP-2 (0.25 +/- 0.07 DU; P = N.S.) or IGFBP-1 (0.27 +/- 0.06 DU; P = N.S.). In summary, after CLP there was a reduction in both circulating and hepatic IGF-I mRNA levels associated with a specific and differential regulation of hepatic IGFBP-1, -2 and -3 mRNA levels. Although we cannot eliminate a possible effect of surgical stress combined with malnutrition, our results suggest that these changes are a specific effect of sepsis rather than simply a result of surgical stress or poor nutrition alone.

Growth hormone treatment in hypopituitary GH deficient adults reduces circulating cortisol levels during hydrocortisone replacement therapy.

OBJECTIVES: Patients with GH deficiency frequently have multiple hormone deficiencies and require hydrocortisone replacement. We have investigated whether GH treatment alters circulating cortisol levels in hypopituitary patients receiving stable replacement therapy. DESIGN: Subjects were studied during 6 or 12 months of s.c. GH at a dose of 0.25 IU/kg/week (0.125 IU/kg/week for the first 4 weeks), and after a wash-out period of at least 2 months off GH (range 2-5 months). PATIENTS: Fourteen hypopituitary patients (2F:12M) receiving stable hydrocortisone replacement and thyroxine, gonadal steroids and bromocriptine therapy as required. MEASUREMENTS: Serum cortisol values were measured throughout the day over 10.5 hours. Thyroid hormones and cortisol binding globulin (CBG) were measured in the baseline sample. Comparisons of the serum cortisol peak after receiving the first dose of hydrocortisone, the time when the serum cortisol peak was obtained, the area under the curve (AUC) for the cortisol values and the levels of unbound cortisol on and off GH therapy were made. The results are expressed as mean +/- SEM. Comparisons were carried out within individuals, using the Wilcoxon signed rank test. A P-value less than 0.05 was considered statistically significant. RESULTS: During GH therapy, there was a significant reduction in the mean cortisol peak (662.2 +/- 61.1 vs 848.0 +/- 58.6 nmol/l; P = 0.001), and in the AUC for cortisol (185.3 +/- 18.3 vs 230 +/- 17.9 nmol/l/10.5h; P = 0.03), but there was no significant change in the time of the cortisol peak (55.7 +/- 7.6 vs 57.8 +/- 4.9 minutes; P = NS). During GH therapy there was a significant reduction in CBG levels (33.64 +/- 1.16 vs 40.86 +/- 1.34 mg/l; P = 0.001); however, no changes were found in the levels of calculated unbound cortisol on and off GH (2.87 +/- 0.38 vs 2.90 +/- 0.30 nmol/l; P = NS). During GH therapy, there was a significant increase in serum triiodothyronine (T3) (1.88 +/- 0.15 vs 1.44 +/- 0.11 nmol/l; P = 0.01), and a significant decrease in thyroxine (T4) levels (74.9 +/- 11.1 vs 97.6 +/- 10.9 nmol/l; P = 0.02) but levels remained within the normal range. No change was observed in serum TSH levels (0.29 +/- 0.13 vs 0.83 +/- 0.71 mU/l; P = NS). CONCLUSIONS: These results suggest that GH therapy in GH deficient adults produces an alteration in the measured serum cortisol profile, with a reduction in concentration of total cortisol in blood after orally administered hydrocortisone. These changes in circulating cortisol probably depend primarily on the fall in CBG levels, as no changes were found in the levels of calculated unbound cortisol on and off GH. Our data show that when measuring circulating cortisol levels, the results should be interpreted with caution in GH deficient patients on GH replacement, and different criteria may have to be applied to the circulating cortisol profile of these patients. The results highlight the importance of ensuring adequate corticosteroid replacement in patients starting GH therapy.

Expression of IGF-I and IGF-binding protein genes in cirrhotic liver.

The liver plays a central role in the IGF-I axis producing the majority of circulating hormone and some of its binding proteins (IGFBPs). Cirrhosis of the liver is characterised by changes in IGF-I and IGFBPs associated with liver fibrosis and regeneration. We have studied steady state levels of mRNA for the genes in the IGF-I axis in normal and cirrhotic human liver, localised the most highly expressed gene, IGFBP-1, and measured circulating IGFBP-3 by radioimmunoassay (RIA), IGFBP-2 and IGFBP-3 by Western ligand blot (WLB), and protease activity for IGFBP-3 in cirrhotic patients. Messenger RNA for IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 was detectable by Northern blotting in normal and cirrhotic liver although there was considerable variation in expression. IGFBP-2 and IGFBP-3 tended to be more highly expressed in cirrhotic liver and IGFBP-1 was more highly expressed in normal liver, although there were no significant differences. In normal liver, in situ hybridisation localised IGFBP-1 to hepatocytes. In cirrhotic liver the regenerating nodules showed expression of IGFBP-1 while there was none in fibrotic tissue. Circulating IGFBP-3 levels were low as measured by RIA and WLB but protease activity was only found in one patient. IGFBP-2 levels, assessed by WLB, were similar to the normal serum pool. Our data show that key mRNAs involved in the IGF-I axis continue to be expressed in cirrhotic liver despite end stage liver disease. The low levels of IGFBP-3 do not appear to be due to reduced gene transcription or increased protease activity.

Regulation of hepatic mRNA levels for the growth hormone receptor in rats with altered thyroid status.

Changes in thyroid status have a major effect on the GH/IGF-I axis. In the rat, there is a single gene for the growth hormone receptor (GHR), that is transcribed into two different sized mRNA transcripts following alternative splicing, one transcript codes for the GHR (4.0-4.5 kb) and the other growth hormone binding protein (GHBP) (1.2-1.3 kb). We have studied the regulation of hepatic GHR gene expression by thyroid hormones in male Wistar rats rendered hypothyroid (n = 6) and hyperthyroid (n = 6) compared to controls (n = 6). By northern blot analysis, two transcripts with an estimated size of 4.2 and 1.2 kb, respectively, were detected in all groups. Hyperthyroidism was associated with a significant increase in the 4.2 kb transcript compared to hypothyroidism (P < 0.05), but no changes were observed in the 1.2 kb transcript. Thus, our results suggest that in the rat hyperthyroidism is associated with either increased hepatic gene transcription or decreased clearance of the 4.2 kb transcript for the GHR compared with hypothyroidism.

Primary hyperaldosteronism due to an adrenal adenoma in a 14-year-old boy.

Conn's syndrome due to an adrenal adenoma is very rare in children. This paper reports a 14-year-old boy with primary hyperaldosteronism due to an adrenal adenoma. His biochemistry data were compatible with either bilateral adrenal hyperplasia or an adrenal adenoma. A dexamethasone test did not suppress aldosterone levels. Venous catheter sampling and 75Se-selenomethylcholesterol scanning suggested that the hyperaldosteronism originated at the right adrenal. Computed tomography showed an 8-mm low-density nodule in the right adrenal gland and magnetic resonance imaging confirmed the nodule which had high signal intensity on T2-weighted images consistent with a functioning adenoma. Surgery confirmed the right adrenal adenoma, and the patient was cured by right adrenalectomy. This case illustrates the difficulty of defining the aetiology of primary hyperaldosteronism and we review the biochemical and scanning techniques available to aid in diagnosis. Hypertension is unusual in children and endocrine causes are very rare, but Conn's syndrome should always be considered in the differential diagnosis.

Expression of IGFBP-1 in normal and cirrhotic human livers.

Cirrhosis of the liver, a condition characterised by hepatocyte regeneration, is also associated with elevated insulin levels and insulin resistance. In animal models hepatic regeneration is associated with increased IGFBP-1 gene expression. Insulin is known to be an inhibitor of IGFBP-1 gene expression and circulating insulin levels in man demonstrate a negative correlation with IGFBP-1 levels. To further our understanding of the regulation of IGFBP-1 in cirrhosis we have studied steady state levels of IGFBP-1 mRNA in human liver from three groups of patients: Group 1, tissue obtained at the time of harvesting donor liver for orthotopic liver transplantation (n = 4); group 2, patients undergoing major liver resection with no histological evidence of chronic liver disease (n = 4); and group 3, patients undergoing orthotopic transplantation for chronic liver failure (n = 9). Simultaneous samples of serum were taken at the time of surgery in some patients and in these patients IGFBP-1 mRNA levels were related to circulating levels of IGFBP-1 and insulin. IGFBP-1 mRNA was detectable in all the human liver samples with the greatest levels seen from the normal livers of group 2 patients. Insulin levels were elevated in the cirrhotic group 3 patients compared to a normal range as were IGFBP-1 levels. There was no relationship between circulating levels of IGFBP-1 and IGFBP-1 gene expression. In conclusion, IGFBP-1 mRNA is present in human adult liver at the time of surgery and also in cirrhotic liver despite high levels of insulin suggesting that there are factors other than insulin regulating IGFBP-1 gene expression.

Changes in hepatic insulin-like growth factor-binding proteins -1, -2 and -3 mRNA levels in rats with altered thyroid status.

Changes in thyroid status have a major effect on the GH/insulin-like growth factor (IGF) axis. The majority of IGF in the circulation is bound to specific IGF-binding proteins (IGFBPs) of which six have been cloned and sequenced. We have studied changes in hepatic gene expression of IGFBP-1, -2 and -3, in male Wistar rats rendered hyperthyroid (thyroxine, 200 micrograms/kg per day) or hypothyroid (propylthiouracil, 0.1% daily). Littermates of the same age were used as controls (n = 6 in each group). Thyroxine was measured by radioimmunoassay, and hepatic IGFBP-1, -2 and -3 mRNA levels by Northern blot analysis using specific rat cDNA probes with a 28S ribosomal probe as a loading control. Mean +/- S.E.M. thyroxine levels were 247.0 +/- 44.5 (hyperthyroid group), < 9.0 (hypothyroid group) and 76.0 +/- 4.5 nmol/l (control group). IGFBP-1 and -2 mRNA levels in the hypothyroid animals compared with the controls were significantly increased, but similar levels of expression were found in thyrotoxic and control rats. IGFBP-3 mRNA levels in hypothyroid animals were decreased, and increased in thyrotoxic animals. Thus, in the adult rat, hypothyroidism is associated with increased hepatic IGFBP-1 and -2 gene expression, but decreased IGFBP-3 gene expression, while in thyrotoxicosis there are normal IGFBP-1 and -2 mRNA levels but increased IGFBP-3 gene expression. These results suggest that there is specific and different transcriptional regulation for IGFBP-1, -2 and -3 in hypo- and hyperthyroid rats.

Influence of thyroid hormones on the GH-IGF-I axis.

There is a complex relationship between thyroid hormones, GH, and the insulin-like growth factors (IGFs). Thyroid hormones act at many sites from the hypothalamic control of GH release to the tissue expression of IGF-I and its binding proteins (IGFBPs). In this review, we present current knowledge of the effects of altered thyroid status on the GH-IGF-I axis, concentrating on the changes seen in IGF-I gene expression and circulating levels of GH and IGFBPs.

Acquired growth hormone resistance in patients with hypercatabolism.

Sepsis, surgery and critical illness are associated with an increased catabolic rate, which if prolonged delays recovery and increases morbidity and mortality. There is evidence that changes in the GH/IGF-I axis are permissive to protein catabolism. Critically ill, septic patients have high basal levels of GH, low levels of IGF-I and its carrier binding protein IGFBP-3, high levels of an inhibitory binding protein, IGFBP-I, and increased serum protease activity which reduces the affinity of IGFBP-3 for IGF-I. Overall there is a reduction in the indirect IGF-I-mediated anabolic actions of GH and an increase in the direct catabolic actions of GH. These physiological changes may be adaptive when a sick patient is fasting; however, the availability of modern intensive care means that these changes are no longer an advantage. GH and IGF-I, in pharmacological doses, promote positive nitrogen balance, in both animal models and man. Preliminary studies with IGF-I in postsurgical patients suggest that it may provide a practical therapy. Future studies need to focus on outcome measures in relation to the use of GH and IGF-I as anabolic therapies.

[Therapeutic effectiveness of the gonadotropin releasing hormone analogue D-Trp-6-LHRH in the treatment of precocious puberty]. / Utilidad terapéutica del agonista de la hormona liberadora de gonadotrofinas D-Trp-6-LHRH en el tratamiento de la pubertad precoz.

Efficacy and safety of a superactive gonadotrophin-releasing hormone analogue (D-Trp-6-LHRH, decapeptyl) was assessed in seven girls, aged two to seven years with precocious puberty (four idiopathic, two associated to McCune-Albright syndrome and one with myelomeningocele). A further case of a seven year old male was treated with a delayed release formulation of the analogue combined with cyproterone acetate for the first two weeks of therapy. Three cases had previously been unsuccessfully treated with cyproterone acetate (2% or medroxyprogesterone (1) but this conventional therapy was discontinued three months prior entering the trial. Decapeptyl was given at a dose of 100 mcg sc daily for 10 days, followed by a dose of 1-2 mcg/kg daily thereafter. One patient required a sustained dose of 7 mcg/kg for effective control. The male patient received a biodegradable depot preparation of decapeptyl at a dose of 1.5 mg IM monthly, calculated to release circa 100 mcg of the analogue daily. He was also treated with cyproterone acetate. 100 mg/m2/day 15 days before and for two weeks during decapeptyl administration. Treatment was well tolerated without significant side effects. After six months on treatment, both LH and FSH levels were undetectable and showed no response to LHRH. Plasma oestradiol levels were reduced from 230 +/- 40 to 13 +/- 4 pg/ml. Total testosterone in the male patient was suppressed from 7 ng/ml to undetectable levels. This was accompanied by a cessation in the progression of the development of secondary sexual characteristics. All female patients developed amenorrhoea and their Tanner stage regressed to I or prepubertad after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)