ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02309.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02310.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE We determined serum sex hormone‐binding globulin (SHBG), serum dehydroepiandrosterone sulphate, serum oestradiol and serum testosterone and its fractions in girls with premature thelarche.DESIGN Blood was drawn from girls with recently diagnosed (3–12 weeks) premature thelarche. Serum was kept frozen for at least one year before hormonal determination to exclude precocious puberty by clinical evaluation. PATIENTS Seventeen girls with premature thelarche aged 0.83–7.16 years were studied, and compared with a group of 22 normal prepubertal girls.MEASUREMENTS SHBG was measured by saturation analysis and serum dehydroepiandrosterone sulphate, serum total oestradiol and serum total testosterone were determined by radioimmunoassay. Non‐SHBG‐bound testosterone and free testosterone were calculated from an equation derived from the law of mass action.RESULTS Median serum SHBG in premature thelarche was 137 nmol/l (range 64–221), significantly higher than in normal controls, 93.7 (32–172) (P<0.05) non‐parametric test of medians. Serum SHBG decreased significantly with age in controls but not in premature thelarche. No difference was found in serum dehydroepiandrosterone sulphate. Median serum total testosterone (0.34 nmol/l, 0.17–0.97), median serum non‐SHBG‐bound testosterone (0.04 nmol/l, 0.02–0.10) and median free testosterone (2.2 pmol/l, 1.0–4.5) were significantly lower in premature thelarche than in control (P<0.001).CONCLUSIONS Serum SHBG is high and bioavailable T is low in girls with premature thelarche. This might alter the oestrogen/and

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02311.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE We determined the effect of 3 months of daily, 40 mg oral testosterone undecanoate on growth, body composition, hand grip and quadriceps muscle strength, and total free‐living daily energy expenditure in boys with constitutionally delayed puberty.DESIGN Double blind, placebo controlled study.PATIENTS Eighteen boys with constitutionally delayed puberty, mean (SD) age 13.2 (1.6) years.MEASUREMENTS Body composition measurements were made by skinfold thickness, bloelectrical impedance and stable isotope dilution (H214O) methods. Energy expenditure was assessed by the doubly‐labelled water (2H213O) technique.RESULTS Height velocity increased from 5.4 (0.8) to 8.1 (0.6) cm/year (P<0.05) in the 3 months after active therapy. Fat‐free mass increased more with therapy (2.7 (0.3) kg) over the 6‐month study period than with placebo (1.7 (0.4) kg,P<0.5). Height velocity increases correlated with daily increases in fat‐free mass (r= 0.68,P= 0.005) in the study group as a whole. Energy expenditure and muscle strength increased similarly in both groups. Predicted adult height decreased in the group which was treated with testosterone undecanoate.CONCLUSIONS Testosterone undecanoate (40 mg daily for 3 months) significantly increased height velocity and fat‐free mass velocities after 6 months but not muscle strength, endurance or total daily energy

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02312.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE Determine the sequence of the androgen receptor gene in men with impaired responsiveness to androgens in order to identify the molecular basis of their under‐virilization.DESIGN Blood samples were used as the source of genomic DNA. Portions of the androgen receptor gene were amplified by polymerase chain reaction and sequenced.PATIENTS Samples were obtained from three patients and five normal fertile controls. Patients were all 46 XY and were undervirilized with ambiguous external genitalia, gynaecomastla and infertility.MEASUREMENTS Total cellular DNA was purified from peripheral blood leucocytes. Pairs of ollgonucleotide primers designed to flank the individual exons of the androgen receptor gene were synthesized. The specific regions of the androgen receptor were amplified from the samples of cellular DNA by polymerase chain reaction. Amplified DNA was purified, sequenced and compared to the published sequence.RESULTS In all three patients point mutations in the androgen receptor gene were detected but no defects were detected in samples from normal controls. In two of the patients, an identical single nucleotide change from G to T was detected. This nucleotide was within the codon for amino acid 866 and would change it from valine to leucine. Amino acid 866 is found within an area of the steroid binding domain thought to be involved in receptor dimerization. Within the repetitive sequence of exon I patient 1 had 21 glutamine residues and patient 2 had 25. In the third patient a single change of G to A would result in incorporation of lysine in place of a conserved arginine residue at position 607 within the second zinc finger of the DNA binding domain. The sequence of the androgen receptor gene of the mother of the third patient revealed her to be heterozygous for the same defect.CONCLUSION Patients 1 and 2 are unrelated although they have an identical point mutation in their androgen receptor gene. A patient with complete androgen insensitivity syndrome has been reported to have a defect at the same position causing the amino acid substitution of methlonine for valine. Therefore we confirm that the nature of the amino acid change in the peptide sequence of the androgen receptor as well as its location within the protein, can have a profound effect on the phenotypic severity of androgen resistance. Studies on mutated receptors from individuals with a wide range of degrees of androgen resistance may enable us to construct a map of the key amino acids in the different domains of the protei

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02313.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE The purposes of our study concerning two patients with oestrogen secreting Leydig cell tumour were to determine whether endogenous LH levels are involved in testicular tumour steroidogenesis and whether aromatase activity of oestrogen secreting Leydig cell tumours is directly or indirectly dependent on LH levels.MEASUREMENTS E2and T were evaluated after hCG Injection (5000IU) during 96 hours. Bio and Immuno LH, T, E2, were determined at the basal state and after administration of D‐Trp‐6‐GnRH agonist (3.75 mg) every 3 weeks. The abnormal testis was removed after the third injection and testicular venous blood was collected during the operation. Testicular tumour was incubated with 4‐14C‐T. RESULTS Oestradiol (E2) response to hCG injection (5000 IU) was prolonged and exaggerated while that of testosterone (T) was similar to that of the controls. The aromatase index (E2/T) remained elevated even 96 hours after hCG. Intramuscular injection of the GnRH agonist, D‐Trp‐6‐GnRH (3.75 mg) resulted in a reduction of immunoreactive and bloactive LH. T was decreased to about 10% of baseline levels and E2fell from 240 to 36 pmol/l. In the blood of the spermatic veins collected in the course of surgery, E2levels were found to be lower in comparison with the controls. E2was found to be twofold higher in the spermatic vein draining the tumoral side than in that of the contralateral testis. Incubation of the testicular tumours with 4‐14C‐T, displayed a reduced aromatase activity (conversion of T to E2:0.3 and 0.1% in patients 1 and 2 respectively).CONCLUSIONS The kinetics of E2response to hCG administration would suggest a modification of the regulation of the aromatase activity in this type of oestrogen secreting tumour. A certain endogenous LH level may be necessary to supply a sufficient quantity of T substrate, and to maintain aromatase activity of such Leydig cell tumours secreting oestrogens. These tumours seem to be responsive to e

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02314.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE It has previously been suggested that acromegalic patients treated with the somatostatin analogue octreotide invariably have chronic gastritis. We have examined the prevalence of gastritis in a large group of acromegalic patients, untreated and during treatment with octreotide.DESIGN We studied three groups of acromegalic patients: (A) untreated; (B) octreotide‐treated; (C) a subgroup of these studied both before and during octreotide therapy. PATIENTS Forty‐eight patients, grouped as above, with active acromegaly were examined for the presence of gastritis.MEASUREMENTS Gastroscopy and histological examination of gastric biopsies for the presence of gastritis andHelicobacterorganisms were undertaken. The principal outcome was quantification of the prevalence of gastritis in the various study groups.RESULTS Group A: 10 of the 33 patients (30%) had gastritis before any therapy with octreotide. Group B: 17 of 36 patients (47%) on octreotide treatment for 6–59 months (mean 20.5) had gastritis, and this was present in five out of the sub‐group of eight patients (62%) treated for over 3 years. Group C: three of 21 patients (14%) developed gastritis during treatment with octreotide for between 6 and 23 months (mean 12.4). There was a highly significant association between the presence of gastritis and the presence ofHelicobacter pyloriorganisms.CONCLUSIONS Octreotide therapy of acromegaly may predispose to the development of gastritis, but this remains statistically unproven. Certainly, gastritis is not an invariable consequence of octreotide therapy, even after prolonged periods of treatment. The presence of gastritis is associated withH. pyloriin

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02315.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE We studied the effects of different modes of octreotide therapy on the pulsatile pattern of GH release in an attempt to define better its regulation by growth hormone‐releasing hormone (GHRH) and somatostatin and its effects on IGF‐I plasma levels in acromegaly.DESIGN In six acromegalic patients not cured by previous treatment we compared the 24‐hour GH secretion profiles under basal conditions with subcutaneous (s.c.) bolus injections of 100 μg octreotide every 8 hours and with continuous s.c. Infusions of the same daily dose. Blood samples were taken every 10 minutes over 24 hours followed by a GHRH test (100 μg GHRH i.v.) with blood sampling every 15 minutes for another 2 hours. After a 4‐week interval all patients were treated either by the bolus or continuous mode of octreotide application in a randomized cross‐over design. On day 4 of treatment blood sampling and GHRH test were repeated. Octreotide treatment was withdrawn for another 4 weeks; all patients then received the alternate application mode and were measured under similar conditions.MEASUREMENTS Serum GH and plasma IGF‐I concentrations were analysed by serial array averaging. IGF‐I levels were measured in two different assays with and without previous protein extraction. For GH pulse detection three different algorithms (Cluster, Pulsar, Desade) were applied.RESULTS With both treatments, the initially elevated basal 24‐hour mean serum GH concentrations (58.0 ± 9.7 mU/l mean.SEM) decreased significantly (bolus: 11.5 ± 4.9 mU/l,P<0.001vsbasal; continuous Infusion: 7.6 ± 1.9 mU/l,P<0.001vsbasal) after 4 days. GH suppression was significantly more pronounced following continuous infusion than bolus (P<0.05). IGF‐I plasma concentrations were lowered significantly (P<0.05) with both forms of treatment which did not differ between themselves. Bolus and continuous infusion treatment significantly inhibited (P<0.05) the amplitudes of pulsatile GH release, but did not change the pulse frequency. In two of the patients, GHRH stimulation did not increase GH serum levels suggesting a constitutive activation of adenylyl cyclase.CONCLUSION Continuous subcutaneous octreotide treatment in acromegaly suppresses mean GH levels better than bolus injection. The number of GH pulses remains unaffected by both modes of treatment providing evidence against a somatostatinergic mechanism of pulsatile GH secretion in these patients. The unchanged frequency of pulsatile GH release in the patients unresponsive to exogenous GHRH indicates that this pattern might be independent of hypothalamic GHRH and somatostatin and suggests a pituitary‐derived mechanism for GH pulse

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02316.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE We studied the effects of long‐term in‐vitro exposure of human GH secreting pituitary adenoma cells to octreotide on GH release, intracellular GH concentrations and GH messengerbonuclelc acid (mRNA) levels.DESIGN Human GH‐secreting pituitary adenoma cells were cultured for periods from 4 days up to 3 weeks without or with octreotide (10 PM) and/or bromocriptine (10 nM). The effects of these drugs were measured on GH release, intracellular GH concentrations and intracellular GH mRNA levels.PATIENTS Thirteen patients with GH‐secreting pituitary adenomas were studied. Twelve patients were untreated, one had been pretreated with octreotide (12 weeks, 3 ± 100 μg daily).MEASUREMENTS GH, PRL, α‐subunlt and IGF‐I concentrations in plasma, media and cell extracts were determined by Immunoradiometric or radloimmunoassays. GH mRNA levels were determined by automatic quantification of grain numbers in individual adenoma cells.RESULTS Incubation of the adenoma cells for 4 days with 10 Nm octreotide induced a dose‐dependent inhibition of GH release and a parallel increase (increase varying between 124 and 617% of control) In the intracellular GH levels was observed in six of seven adenomas. In addition, bromocriptine, when effective in inhibiting GH release by the adenomas, also induced an increase in intracellular GH levels. Even after 3 weeks of exposure to 10 nM octreotidein vitrothere was a statistically significant increase in intracellular GH levels (between 191 and 923% of control). Withdrawal of octreotide after 6 days of incubation resulted in a lowering of intracellular GH levels to control values, showing that the octreotide‐induced increase in intracellular GH is reversible. In a 96‐hour incubation with 10 nM octreotide, GH mRNA levels were increased in two, and slightly decreased in one of the three adenomas tested. This effect was time dependent in that there was no significant effect of 10 nM octreotide on GH mRNA levels in a 24‐hour incubation.CONCLUSIONS (1) Long‐term in‐vitro exposure of GH‐adenoma cells to octreotide causes an increase in intracellular GH levels in the majority of the adenomas, probably because of an increase in GH mRNA levels in the adenoma cells; and (2) this considerable increase in intracellular GH levels may be one of the explanations for the relatively poor effect of octreotide on tumour shrinkage In patients with GH

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02317.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

OBJECTIVE Growth hormone receptor status was assessed in children with idiopathic short stature by evaluating plasma growth hormone‐binding protein before and under GH therapy.DESIGN Among 22 children presenting idiopathic short stature, 15 were randomly selected to be treated with GH (1.2 IU/kg/week); they were studied before and under GH therapy. Untreated patients served as a control group for age and GH effect.PATIENTS Twenty‐two prepubertal children, aged 5–11 years, were studied. They presented growth retardation of ‐2.8±0.1 SDS (mean . SEM). All had normal GH secretion and their mean IGF‐I plasma level was normal.MEASUREMENT Growth hormone‐binding protein was measured using high pressure liquid chromatography gel filtration. The specific binding of125I‐hGH to the growth hormone‐binding protein was expressed as a percentage of the total radioactivity.RESULTS Specific binding of125I‐hGH to the high affinity growth hormone‐binding protein was low with a mean . SEM value of 11.1 . 0.9% of radioactivity. In the treated group, growth hormone‐binding protein increased significantly after 3 months of treatment; It reached 21.1 . 1.0% of radioactivity (mean . SEM) in the eight children who have been treated for 18 months. In the seven untreated children, the growth hormone‐binding protein value Increased to 16.2.1.1% after 18 months; this value is significantly lower than that found in the GH‐treated children, demonstrating that the GH effect Is greater than the age‐related increase in the growth hormone‐binding protein. A positive correlation was found between IGF‐I plasma levels and growth hormone‐binding protein and also between growth velocity and growth hormone‐binding protein.CONCLUSIONS The low growth hormone‐binding protein and the response to high doses of GH suggest partial GH resistance at the receptor level, in this group of

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1992.tb02318.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY