摘要:

SummaryThe demands of fetal growth lead to an adaptation of maternal homeostasis In order to provide the required calcium from enhanced intestinal absorption rather than from mobilization of maternal skeletal reserves. In large part this adaptive process depends on the interrelationship between PTH and 1,25(OH)2D which shows quantitative rather than qualitative changes from the non‐pregnant state. In contrast the maintenance of fetal mineral homeostasis largely depends on PTHrP which regulates active placental calcium transfer and the calcium fluxes across the kidney and bone. The major source of PTHrP is the fetal parathyroid gland although some is provided by the placenta. It may be this latter component which passes Into the maternal circulation where It may play a role in calcium homeostasis by acting through the PTH recepto

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02052.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SummaryOBJECTIVEIGF‐I rises in normal adolescence and in central precocious puberty (CPP), secondary to a rise in sex steroids and GH. The aim of this study was to examine changes in serum IGF‐I and its major binding protein IGFBP‐3 after pharmacological arrest of puberty.PATIENTS AND MEASUREMENTSTen girls diagnosed for CPP were evaluated before and during the first 3 months of GnRH analogue (GnRHa) therapy aimed at Suppression of the gonadal axis. Serum IGF‐I was measured by immunoradiometric assay (IRMA) and IGFBP‐3 by both IRMA and Western ligand blotting (WLB).RESULTSSerum IGF‐I was markedly higher in patients with CPP as compared with age matched controls (48.8 ± 6.5vs23.1 ± 4.9 nmol/l,P<0.01). While GnRHa therapy caused serum oestradiol levels to return to pre‐pubertal levels in all 10 patients, serum IGF‐I levels decreased only minimally after 1, 2 or 3 months of therapy (43.2 ± 5.6, 42.3 ± 6.4 and 44.1 ± 7.2 nmol/l respectively). Serum IGFBP‐3 levels as determined using IRMA were also higher in CPP compared with age matched controls (4.70 ± 0.37vs3.71 ± 0.42mg/l,P<0.01). These differences were also evident when measured by WLB. GnRHa therapy caused a small and insignificant decrease in serum IGFBP‐3 levels after 1, 2 or 3 months of therapy (4.57 ± 0.33, 4.48 ± 0.4 and 4.42 ± 0.3 mg/l respectively).CONCLUSIONSThe lack of suppression of both IGF‐I and IGFBP‐3, despite therapy which halts puberty and slows growth velocity, suggests that steroids may be involved In the Induction of changes in the GH/IGF‐I axis but

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02053.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SummaryOBJECTIVEUnlike IGF‐I and its principal binding proteins, data regarding IGF‐II levels have not been well defined in normal subjects and those with insulin‐dependent diabetes mellitus (IDDM). We have therefore measured IGF‐II, as well as IGF‐I, and IGFBP‐3, levels In a large cohort of subjects with IDDM and in age/sex matched controls.PATIENTSOne hundred and fourteen patients with IDDM (57 males, 57 females) and 89 control subjects (49 males, 40 females).MEASUREMENTSRandom blood samples were obtained from each subject for the measurement of IGF‐II, IGF‐I and IGFBP‐3 levels.RESULTSMean values of IGF‐II (±SEM) were 630 (±27.8) μg/l and 646 (±32.3) μg/l in female and male controls, compared to 569 (±23.3) μg/l and 623.3 (±28.1) μg/l in female and male diabetics respectively. IGF‐II levels did not differ significantly between the sexes or show any change with transition through puberty in either control or diabetic groups. In contrast, IGF‐I levels increased through puberty peaking at stages 3–5 in controls (P<0.001) and G4–5 (P= 0.002) in diabetic males but not females. IGF‐I levels in all diabetics were generally lower than in controls, differences reaching significance at G4–5 in males (P= 0.002) and B5 in females (P= 0.002). IGFBP‐3 levels did not show any variation with puberty stage in diabetics, in contrast to controls where levels increased, peaking at G4–5 in males (P= 0.001) and B3 in females. IGFBP‐3 levels were lower in diabetics of both sexes and at all stages compared to controls (Prange 0.047 to<0.001). Multiple regression analysis revealed significant correlations between IGF‐II and IGFBP‐3 (F= 20.1,P=<0.001) and reaffirmed previously observed associations for IGF‐I and IGFBP‐3. The sum of IGF‐I and IGF‐II (expressed as nmol/l) correlated with IGFBP3;r= 0.47 in controls and 0.60 in diabetics.CONCLUSIONSInsulin‐dependent diabetes mellitus is not associated with any significant changes in IGF‐II levels during puberty. The binding of IGFBP‐3 for both IGF

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02054.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SummaryOBJECTIVEIn patients with congenital GH deficiency (GHD), magnetic resonance Imaging (MRI) has revealed morphological abnormalities such as pituitary hypoplasia, absence of the stalk and ectopia of the posterior pituitary (PPE). Our study was aimed at investigating the possible relationship between neuroradioiogical Images and the presence of Isolated GH or multiple pituitary hormone deficiency.DESIGNWe studied 121 patients, aged 0.3–25 years, with Isolated GHD (IGHD, 81 cases) or multiple pituitary hormone deficiency (MPHD, 40 cases). Of 81 IGHD patients, 50 were at prepubertal and 22 at pubertal age, while 9 had a delayed onset of puberty. Out of 40 MPHD patients, 25 were at prepubertal age and 15 at the age of puberty.RESULTSPituitary hypoplasia, defined as a gland with a height of less than −2 SD for age, was observed more frequently in prepubertal (66%) than pubertal (18%) IGHD patients. It was also found in the majority of MPHD patients of prepubertal (76%) and pubertal age (80%), and of IGHD patients with delayed onset of puberty (100%). Mean ± SEM pituitary height was significantly lower (P<0.001) In both prepubertal IGHD (−2.70 ± 0.20 SD) and MPHD children (−3.10 ± 0.39 SD) than in IGHD patients with normal onset of puberty (−1.55 ± 0.2 SD). A significantly greater pituitary height was observed in IGHD patients with normal onset of puberty (−1.55 ± 0.20 SD) than In MPHD patients at the age of puberty (−4.38 ± 0.61 SD,P<0.001) and in IGHD subjects with delayed onset of puberty (−4.06 ± 0.41 SD,P<0.001). An Important Increase (P<0.02) in the height of the pituitary gland was found in 6 of the 9 patients with delayed puberty when they were re‐evaluated after completing their spontaneous pubertal development. The frequency of other MRI abnormalities (PPE, stalk transection) was significantly higher in MPHD patients than In IGHD patients (P<0.001).CONCLUSIONOur results confirm the usefulness of MRI In the evaluation of children affected by GH deficiency. The association of gland hypoplasia with other MR abnormalities could suggest the presence of multiple anterior pituitary deficiencies. Finally, puberty seems to play an important role in the increase of pituitary size in multiple pituitary hormone deficiency and isolate

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02055.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SummaryOBJECTIVESProlonged GH deficiency Induces alterations In bone metabolism and structure. Trials In GH deficient adults (GHDA) employing high dose GH replacement therapy produced conflicting results, and caused several adverse effects. This prompted us to study the effects of rhGH treatment on bone metabolism and structure at lowest doses so far used.DESIGNNine GHDA (7 males and 2 females, aged 25–34 years) were studied before, after 12 months of rhGH treatment (70 μg/kg/week, divided Into 3 Injections, administered s.c. at 2000 h on Monday, Wednesday and Friday, respectively) and after 12 months off therapy.MEASUREMENTSSerum IGF‐I, IGFBP‐3, bone‐gla‐protein (BOP), procollagen‐III (PIIINP), PTH and vitamin D, and bone mineral density (BMD) at proximal (Prox) and ultradistal (Dist) sites of the radius were measured.RESULTSBefore treatment, IGF‐I, IGFBP‐3, BGP and PIIINP levels, as well as both Prox and Dist BMD, were significantly lower than In controls. GH therapy normalized all these parameters, except for the Dist value, which nonetheless Increased. No significant changes In PTH and vitamin D variation were seen. After 12 months off therapy all parameters returned to pretreatment levels.CONCLUSIONSOur results suggest that 12 months of rhGH treatment at the lowest doses so far used normalizes bone metabolism and cortical bone density, and Improves trabecular bone density without causin

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02056.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SummaryOBJECTIVESPatients 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.DESIGNSubjects 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).PATIENTSFourteen hypopituitary patients (2F:12M) receiving stable hydrocortisone replacement and thyroxine, gonadal steroids and bromocriptine therapy as required.MEASUREMENTSSerum 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 OH 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.RESULTSDuring OH 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 ± 1.34mg/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 OH therapy, there was a significant increase In serum trilodothyronine (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/I;P =NS).CONCLUSIONSThese results suggest that OH 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 erally 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 OH deficient patients on GH replacement, and different criteria may have to be applied to the circulating cortlsol profile of these patients. The results highlight the importance of ensuring adequate corticosteroid replacement in patien

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02057.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SummaryOBJECTIVEThe central serotoninergic system is known to modulate the activity of the hypothalamic‐pituitary‐adrenal axis, but the effect of fenfluramine, a serotonin reuptake inhibitor, on ACTH and cortisol secretion is not well understood. We have therefore evaluated its effects on the hypothalamic‐pituitary‐adrenal axis in healthy controls.DESIGNEpisodic secretion of ACTH and cortisol was Investigated in 6 healthy volunteers under basal conditions and again during treatment with 20 and 60 mg fenfluramine given orally every 8 hours. On all occasions blood samples were obtained at 10‐minute Intervals for 24 hours and the mode of hormone secretion was analysed by three different methods (PULSAR, CLUSTER, DESADE). In addition ACTH and cortisol responses to CRH were tested at the end of the sampling period.RESULTSAt the lower dose fenfluramine had no effect on ACTH and cortisol secretion. At the higher dose a significant increase of mean plasma ACTH (+ 85%) and cortisol (+129%) levels as well as of urinary free cortisol secretion (+44%) was observed. Fenfluramine did not modulate the frequency, but increased the amplitudes of ACTH and cortisol secretory episodes. ACTH and cortisol responses to CRH injection remained unchanged. Maximum plasma levels ofd‐fenfluramine andd‐nortenfluramine were documented 2–4 hours after the ingestlon of the drug.CONCLUSIONFenfluramine stimulates the activity of the hypothalamic‐pituitary‐adrenal axis at a suprapituitary level by modulating the amplitude of ACTH and cortis

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02058.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02059.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02060.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

SummaryOBJECTIVEThere are advantages and disadvantages with all of the presently available types of testosterone replacement for hypogonadal men. We performed this investigation to establish detailed data about the pharmacokinetics, pharmacodynamics, feasibility and side‐effects of subcutaneously implanted testosterone (T) pellets.DESIGN AND MEASUREMENTIn a single‐dose, open‐label, non‐randomized study, 6 T‐pellets, each containing 200 mg of fused crystalline T, were Implanted in the subdermal fat tissue of the lower abdominal wall of 14 hypogonadal men. Blood samples for determination of T, LH, FSH, 5α‐dihydrotestosterone (DHT), sex hormone binding globulin (SHBG) and oestradiol (E2) were obtained at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48 hours and on day 21 after implantation and then every 3 weeks until day 189, and on days 246 and 300 during follow‐up. In another 36 hypogonadal men the feasibility and side‐effects of T‐pellets were evaluated.PATIENTSFourteen patients participated in the detailed pharmacokinetic study and another 36 patients in the assessment of feasibility and side‐effects. All patients (age range 18–61 years) suffered from primary or secondary hypogonadism (T<3.6nmol/l).RESULTSThe pharmacokinetic study in 14 hypogonadal men revealed an initial short‐lived burst release of T with a peak concentration of 49.0 ± 3.7 nmol/l at 0–5 ± 0.13 days which was followed by a stable plateau lasting until day 63 (day 2, 35.2 ± 2.3; day 63, 34.8 ± 2.6 nmol/l). Thereafter serum T gradually declined and was close to baseline concentrations on day 300. Apparent terminal elimination half‐life (t1/2) was 70.8 ± 10.7 days and apparent mean residence time 87.0 ± 45 days. On average, serum T was below 10 nmol/l after 180 days. Absorption of T followed a zero‐order release kinetic with an absorption half‐time of 74.7 days (95% confidence Interval: 71.1–78.5) and was almost complete by day 189 (95.9 ± 0.84%). Serum DHT and E2were significantly elevated from day 21 to day 105 and correlated significantly with T (DHT, r = 0–65,P<00001, E2, r = 067,P<0.0001). SHBG was significantly decreased from day 21 to day 168. In 6 men with primary hypogonadism T suppressed LH and FSH to the eugonadal range from day 21 to 126 and 42 to 105, respectively, with nadirs occurring at day 84 (LH) and day 63 (FSH). LH and FSH were highly inversely correlated with T (r=−0.47 and −0.57).The only side‐effect observed during 112 implantations in the total group of 50 men were 6 local infections (5.4%) leading to extrusion of 5 pellets In 3 men. When given the choice, all patients except one preferred T‐pellets to their previous T medication for permanent substitution therapy.CONCLUSIONT‐pellets are the androgen formulation with the longest biological action and strongest pharmacodynamic efficacy in terms of gonadotrophin suppression. The pharmacokinetic features are advantageous compared to ot

ISSN:0300-0664    

DOI:10.1111/j.1365-2265.1996.tb02061.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY