bluuebunny/crossref_metadata_2025_split huggingface dataset:
A very high dose dexamethasone suppression test for differential diagnosis of Cushing's syndrome
Authors: Al‐Saadi  , Diederich  , Oelkers  
Published: March 2003

OBJECTIVEThe high‐dose dexamethasone (dex) suppression test of cortisol secretion (8×2 mg dex over two days or 8 mg overnight) is a mainstay in the differential diagnosis of Cushing's syndrome (CS). In some patients with pituitary Cushing's disease (CD), however, plasma cortisol is not suppressed to <50% of control by 8 mg of dex. We therefore hypothesized that a higher dose of dex might produce more effective suppression of cortisol secretion in CD.DESIGN AND SUBJECTSWe routinely tested the diagnostic efficacy of a very high dose of dex (32 mg, i.e. 4×8 mg in 24 hours) in comparison with the 8 mg overnight dex test in a population of patients with CD, in which an unusually high percentage was refractory to 8 mg dex. End points were the suppression of plasma cortisol, plasma ACTH and urinary free cortisol (UFC) to <50% of control. Corticotrophin releasing hormone (human CRH) tests were also performed.RESULTSEleven out of 26 (11/26) patients with CD (42%), among them six with pituitary macroadenomas, failed to show suppression of plasma cortisol after 8 mg dex. Five out of 19 patients (26%) with CD failed to suppress after 32 mg dex. Only 3/19 (16%) failed to suppress UFC after 32 mg dex. In non‐ pituitary CS (n=11), only one patient with macronodular adrenal hyperplasia showed significant suppression of plasma cortisol, but not UFC, after 32 mg dex. ACTH suppression after 8 or 32 mg dex was often less pronounced than that of cortisol and was of no diagnostic value. Cortisol stimulation by 23% after hCRH injection differentiated 100% of patients with CD from other forms of CS.CONCLUSIONIn this series, the hCRH test was the most reliable test for the differential diagnosis of Cushing's syndrome. The 32 mg dexamethasone test with measurement of urinary free cortisol was clearly superior to the 8 mg test and to other aspects of the very high dose dexamethasone test. It can be recommended for ‘non‐suppressible’ patients with ACTH‐dependent Cushing's syndrome and can be performed on outpatients.
Enhanced growth hormone (GH) responsiveness to GH‐releasing hormone after dietary restriction in patients with Cushing's syndrome
Authors: Leal‐Cerro  , Venegas  , Garcia‐Pesquera  , Jimenez  , Astorga  , Casanueva  , Dieguez  
Published: March 2003

OBJECTIVEIn patients with Cushing's syndrome, decreased growth hormone (GH) secretion is observed although the basic mechanism is not yet understood. A short‐term hypocaloric diet is known to increase both spontaneous and GHRH‐stimulated GH secretion in normal subjects. In order to gain further insight into the altered GH secretion in patients with Cushing's syndrome, we assessed the effect of a short‐term hypocaloric diet on GH responses to GHRH in these patients.DESIGNTwo GHRH tests (1 μg/kg i.v.) were performed, the first under basal conditions (normocaloric diet) and the second after a 3‐day hypocaloric diet (650 cal/day).PATIENTSSix female patients with untreated Cushing's disease.MEASUREMENTSPlasma GH levels were measured by immunoradiometric assay.RESULTSGHRH‐induced GH release was impaired in patients with Cushing's disease on a normal diet (mean peak 12.4 ± 6.4 mU/l, area under the curve (AUC) 744 ± 332 mU/l/120 min). Following a hypocaloric diet, GH responses to GHRH were markedly enhanced in the same group of patients (mean peak 46.2 ± 14.8 mU/l, AUC 3142 ± 1032 mU/l/120 min, P < 0.05).CONCLUSIONSThis study demonstrates that in patients with Cushing's disease the somatotroph hyporesponsiveness to growth hormone releasing home is improved after a short‐term hypocaloric diet. Therefore, blunted growth‐hormone secretion in chronic hypercortisolism is a potentially reversible state and the secretory capacity of the somatotroph appears not to be severely compromised in patients with Cushing's disease.
Exaggerated 17‐hydroxyprogesterone response to short‐term adrenal stimulation and evidence for CYP21B gene point mutations in true precocious puberty
Authors: Cisternino Mariangela , Dondi Elisabetta , Martinetti Miryam , Lorini Renata , Salvaneschi Laura , Cuccia Mariaclara , Severi Francesca 
Published: March 2003

OBJECTIVEFollowing the observation of two patients affected by true precocious puberty who went on to develop polycystic ovary syndrome (PCOS) and who were found to be heterozygotes (carriers) for 21‐hydroxylase deficiency (21‐OHD), we decided to evaluate the frequency of heterozygosity for adrenal 21‐OHD in patients with true precocious puberty.STUDY DESIGNWe investigated 32 girls affected by true precocious puberty, by the single‐dose ACTH stimulation test, HLA typing and the molecular analysis of the CYP21B gene encoding for the 21‐OH enzyme, in order to detect gene deletions or point mutations. Twenty‐eight cases were on LHRH analogue treatment and the remaining four, untreated owing to parental refusal, were investigated 0.5–1.5 years after spontaneous menarche.RESULTSAfter ACTH testing, 13 out of the 32 (41%) cases displayed higher 17‐hydroxyprogesterone (17‐OHP) levels than normal but less than those found in patients affected by nonclassical adrenal hyperplasia (CAH); these levels were similar to those observed in obligate heterozygotes for CAH due to 21‐hydroxylase deficiency (21‐OHD). HLA typing showed a significantly increased frequency of the HLA alleles A28 and B14 which are peculiar to the HLA haplotypes of nonclassical CAH due to 21‐OHD. Molecular analysis of the CYP21B gene showed that in four out of the 10 tested patients with an exaggerated 17‐OHP response there were heterozygous point mutations of the CYP21B gene. In contrast, no CYP21B gene abnormalities were detected in the eight tested patients with normal 17‐OHP. No differences were found between carriers and non‐carriers of the 21‐OHD with regard to age at onset of precocious puberty, clinical features, bone age acceleration and gonadal suppression induced by LH‐RH analogue treatment. Two out of the four untreated patients who were investigated after menarche were found to be carriers of the 21‐OHD; these girls showed signs of androgen excess, irregular menses and polycystic ovaries.CONCLUSIONSA high frequency of heterozygosity for adrenal steroid 21‐OHD was found in our patients with true precocious puberty. This adrenal defect does not seem to influence the pattern of central precocious puberty, but these patients require long‐term follow‐up as they might go on to develop polycystic ovary syndrome (PCOS). Whether or not heterozygosity of the 21‐OHD may be related to the premature activation of the hypothalamo‐pituitary‐gonodal axis remains to be defined.
Reduced growth hormone (GH) responsiveness to combined GH‐releasing hormone and pyridostigmine administration in the Prader–Willi syndrome
Authors: Grugni  , Guzzaloni  , Moro  , Bettio  , De Medici  , Morabito  
Published: March 2003

OBJECTIVEIt is unclear whether the blunted GH secretion in Prader–Willi Syndrome (PWS) is a true deficiency, or merely secondary to obesity. We have investigated the role of obesity in the blunted GH secretion in PWS.DESIGNWe studied the GH response to a combined administration of GHRH (1 μg/kg i.v. at 0 min) and pyridostigmine (PD) (60 and 120 mg by mouth for children and adults, respectively, at time −60 min), as well as the baseline IGF‐I levels, in a group of patients with PWS. Two different control groups were studied with GHRH+PD using the same doses and methods as above: prepubertal and pubertal obese subjects, and prepubertal short normal children. Moreover, in 14 patients with PWS and in the group of short normals the GH response to at least two stimulation tests (insulin tolerance test, clonidine, L‐dopa, arginine) had been previously determined.PATIENTSTwenty‐two PWS patients (10 males and 12 females), 21 with essential obesity (11 males and 10 females), and eight short normal children (4 males and 4 females) were studied after obtaining informed consent.MEASUREMENTSBlood samples were taken at −60, −30 and 0 min and then 15, 30, 45, 60, 90 and 120 min after GHRH administration. Serum GH was measured in duplicate by IRMA, and IGF‐I by RIA after acid ethanol extraction. Statistical analysis was performed by t‐test for unpaired data, and analysis of variance for parametric or nonparametric data, where appropriate.RESULTSThe GH response to GHRH+PD was significantly lower in PWS patients (AUC: mean  ± SE: 599 ± 99 μg/l/h) if compared with either short normal children (3294 ± 461 μg/l/h: P < 0.0001) or obese subjects (1445 ± 210 μg/l/h: P < 0.005). Low IGF‐I concen_trations were found in all PWS patients, so that PWS group had mean IGF‐I levels significantly lower than the other groups.CONCLUSIONSOur results showed that subjects with PWS had a reduced GH responsiveness to GHRH+PD associated with subnormal IGF‐I levels. These findings suggested that short stature in PWS may be at least partially correlated to the presence of GH deficiency, and that impaired GH secretion is not secondary to obesity.
Beneficial effects of long‐term GH replacement therapy on quality of life in adults with GH deficiency
Authors: Wirén Lena , Bengtsson Bengt‐Åke , Johannsson Gudmundur 
Published: March 2003

OBJECTIVEQuality of life tends to be adversely affected in adults with GH deficiency. The aim of this study was to examine changes in quality of life in a large group of GH‐deficient adults receiving long‐term GH replacement therapy.DESIGNThe study was conducted in two stages. The first stage was a prospective, open trial of GH replacement therapy in 71 GH‐deficient adults, during which GH was administered for 20–50 months. For the second stage, a further 90 patients were recruited to create a population of 161 GH‐deficient adults, all of whom had received GH replacement therapy for more than 12 months. This population was investigated retrospectively, using a questionnaire designed specifically for this study.PATIENTSAll patients were GH deficient and showed a peak GH response of less than 3.0 μg/l during an insulin tolerance test in which blood glucose levels dropped to 2.2 mmol/l or below.MEASUREMENTSThe quality of life of patients in the prospective stage was assessed using the Nottingham Health Profile (NHP) parts I and II, and the Psychological General Well‐Being (PGWB) index. In the retrospective study patients completed a specially developed questionnaire, designed to determine whether changes in quality of life were sudden or gradual, and whether quality of life continued to change after GH had been administered for more than 12 months.RESULTSIn the prospective stage, mean overall score on the NHP I improved significantly during the first 6 months of GH therapy, and remained at its new level thereafter. Scores in all areas of the NHP II improved significantly between baseline and 20–50 months, as did the total score and five of six area scores on the PGWB index. The total PGWB score and three area scores improved significantly between 6 or 12 months and 20–50 months. In the retrospective stage, 92.7% of the patients reported that they had experienced positive effects of GH therapy. In 30.3% of patients, however, such effects did not become apparent until GH had been administered for more than 6 months. Almost 60% of patients felt that their condition was still improving.CONCLUSIONSThese results indicate that the previously reported beneficial effects of GH therapy on quality of life in GH‐deficient adults are sustained during long‐term therapy. In addition, they suggest that, once started, GH therapy should be continued for at least 6 months before judgements are made regarding its efficacy in improving quality of life.
Serum growth hormone (GH) binding protein, IGF‐I and IGFBP‐3 in patients with β‐thalassaemia major and the effect of GH treatment
Authors: Low L. C. K. , Postel‐Vinay M. C. , Kwan E. Y. W. , Cheung P. T. 
Published: March 2003

OBJECTIVELevels of IGFI have been shown to be low in transfusion‐dependent thalassaemia and there is preliminary evidence to suggest that this may be reversed by GH treatment. In this further study we have evaluated serum growth hormone (GH) binding protein (GHBP), IGF‐I and IGFBP‐3 in patients with β‐thalassaemia major and the effects of GH treatment on these various parameters.PATIENTSFifty‐six transfusion dependent patients with β‐thalassaemia major without GH deficiency between 2 and 20 years of age were studied. Thirteen non‐GH deficient patients with heights of −1.5 SD or more were treated with GH at a dose of 0.14 IU/kg/day subcutaneously for 1 year.MEASUREMENTSSerum GHBP, IGF‐I and IGFBP‐3 were measured in all the patients. In the 13 patients treated with GH, these serum parameters were measured before and after 3, 6 and 12 months of treatment.RESULTSThe mean serum GHBP concentrations were normal in both prepubertal and pubertal children but the serum IGF‐I and IGFBP‐3 concentrations were low throughout childhood and adolescence. There was a significant correlation between serum IGF‐I and IGFBP‐3 concentrations (r = 0.79; P = 0.0001) but there was no correlation between the height SDS of the patients with serum GHBP, IGF‐I or IGFBP‐3 levels. GH treatment in the 13 patients resulted in significant growth acceleration associated with a significant rise in the serum IGF‐I and IGFBP‐3 and a significant fall in serum GHBP concentrations.CONCLUSIONSThe low serum concentrations of IGF‐I and IGFBP‐3 in the presence of normal GH reserve and serum GHBP concentrations in patients with β‐thalassaemia suggest a state of partial GH insensitivity at the post‐receptor level. This partial GH insensitivity state can be overcome by supraphysiological doses of exogenous GH. The lack of correlation of IGF‐I, IGFBP‐3 and GHBP with height SDS of the patients imply that the growth failure commonly observed in patients with β‐thalassaemia major may not be specifically related to dysregulation of the GH–IGF‐I axis. GH therapy resulted in significant increase in serum IGF‐I and IGFBP‐3 but a significant fall in GHBP.
Effects of flutamide on pituitary and adrenal responsiveness to corticotrophin releasing factor (CRF)
Authors: De Leo V. , La Marca A. , Lanzetta D. , Cariello P. L. , D'Antona D. , Morgante G. 
Published: March 2003

OBJECTIVEFlutamide is a non‐steroid antiandrogen that specifically blocks the androgen receptor. We have investigated the effect of flutamide treatment on the adrenal androgen response to corticotrophin releasing factor (CRF) in eight patients with polycystic ovary syndrome (PCOS).PATIENTSEight women with moderate to severe hirsutism, ranging in age from 19 to 23 years were enrolled in the study. Basal hormonal pattern showed anovulatory cycles, increased concentrations of LH, androstenedione and testosterone and increased LH/FSH ratio. A baseline ultrasound scan revealed polycystic ovaries in all patients. Each received 250 mg of Flutamide twice a day for 6 months.MEASUREMENTSBefore treatment and at the end of the sixth month, women were evaluated for hirsutism score and a CRF test was performed to evaluate ACTH, cortisol and adrenal androgen responses.RESULTSAndrostenedione (Δ4), DHEA‐S, 17‐hydroxyprogesterone, testosterone and free‐testosterone showed significantly reduced responses after six months of flutamide therapy whereas ACTH and cortisol response were similar to those before treatment. Clinical improvement in the degree of hirsutism was observed in all patients. The Ferriman‐Gallwey scores decreased from a mean of 22 ± 2 to 8 ± 1.5.CONCLUSIONFlutamide induces a significant reduction in adrenal androgen response to the CRF test but not in the response of ACTH and cortisol. The finding that flutamide does not alter the pituitary‐adrenal axis shows that flutamide acts by reducing adrenal androgens. These results demonstrate that flutamide is not only effective in the treatment of hirsutism but also reduces adrenal androgen secretion.
The circadian rhythm of leptin is preserved in growth hormone deficient hypopituitary adults
Authors: Kousta Eleni , Chrisoulidou Alexandra , Lawrence Natasha J. , Al‐Shoumer Kamal A. S. , Parker Kim H. , McCarthy Mark I. , Johnston Desmond G. 
Published: March 2003

OBJECTIVELeptin acts as a satiety factor in regulating food intake and body homeostasis, but its regulation is not well defined. Specific leptin receptors have been found in the brain and it has been hypothesized that leptin production by adipose tissue is under neuroendocrine control. A circadian rhythm has been demonstrated with highest leptin levels between midnight and early morning hours. The possibility that hypopituitarism (or pituitary surgery ± radiotherapy) abolishes this leptin rhythm was investigated by measuring serum leptin levels during a 24‐h period in patients with impaired pituitary function.PATIENTS AND DESIGNCirculating leptin levels were measured hourly over 24‐h in 14 hypopituitary patients (8 women and 6 men) using a sensitive and specific radioimmunoassay. Hypopituitarism was the consequence of pituitary tumors treated surgically and/or with radiotherapy. All patients were GH deficient and were receiving conventional replacement with cortisol (n = 13), thyroxine (n = 12) and desmopressin (n = 4) but not with GH.RESULTSA significant diurnal variation in circulating leptin concen_trations was observed in 13 of the 14 patients. The mean (±SEM) leptin levels for 8 women were 51.9 (±10.7) ng/ml and for 6 men 11.0 (±2.0) μg/l. The overall lowest leptin levels (29.3 ± 7.9 ng/ml) were observed at 0830 h after overnight fasting, rising gradually to maximum levels (43.0 ± 9.8 ng/ml) at 0200 h declining thereafter towards fasting values. The mean (±SEM) magnitude of circadian variation in absolute leptin levels from the calculated mean level for each patient was 5.6 (±1.2) ng/ml (8.4 ± 1.4 for women and 1.9 ± 0.3 for men). The mean (±SEM) of the ratio of the amplitude versus mean leptin levels over 24 h for each individual patient was 0.18 (±0.02) (0.19 ± 0.03 for women and 0.18 ± 0.02 for men).CONCLUSIONSA circadian rhythm for leptin is generally present in hypopituitary patients who had undergone pituitary surgery and/or radiotherapy, with the highest serum leptin levels being obtained between midnight and early morning hours. Although some patients had some residual pituitary activity, intact hypothalamic‐pituitary function is not essential for leptin's circadian rhythm.
L‐5‐hydroxytryptophan does not stimulate LH secretion directly from the pituitary in patients with gonadotrophin releasing hormone deficiency
Authors: Lado‐Abeal Joaquin , Graña Maria , Rey Carlos , Cabezas‐Cerrato Jose 
Published: March 2003

OBJECTIVEThere is abundant histological and physiological evidence that serotonin plays a role in the regulation of LH secretion in rats. Studies in human subjects have been few, but their results include the finding that pulsatile administration of L‐5‐hydroxytryptophan (5‐HTP, the immediate precursor of serotonin) amplifies LH secretion in women in the medium‐late follicular phase, and that this effect is not due to 5‐HTP directly inducing LH secretion by the pituitary. We have investigated whether 5‐HTP amplifies LH secretion by enhancing the response of the pituitary to GnRH.PATIENTSSeven patients aged 20–40 years with hypogonadotrophic hypogonadism (HH) of hypothalamic origin (3 men with Kallmann's syndrome, 2 women without anosmia and with GH deficiency, and 2 women with anorexia nervosa).DESIGNTo prime the pituitary, subcutaneous pulsatile GnRH was administered for 7 days at the rate of one 5–20 μg pulse every 90 min. The day before the investigation, this regimen was replaced by 1.5–3 μg intravenous pulses at the same frequency. On the day of the investigation, 3 ml blood samples were taken every 10 min from 0850 to 19.00 hours. After the first two samples, the intravenous GnRH pulse frequency was increased to one per hour and was maintained at this level throughout the rest of the study. The first 4 h of the study acted as a control phase allowing determination of the pituitary response to GnRH. At 1300 h, 75 mg of the aromatic‐L‐amino‐acid decarboxylase inhibitor carbidopa was administered orally; carbidopa does not cross the blood–brain barrier, and prevents peripheral conversion of 5‐HTP to serotonin. At 1600 h, another 75 mg dose of carbidopa was administered, and administration of 8–20 mg pulses of 5‐HTP at a rate of one pulse per hour was begun.MEASUREMENTSLH was determined in triplicate by an immunoradiometric assay (IRMA), and LH pulses identified by means of a program developed in our laboratory.RESULTSWhen pulsatile administration of GnRH was accompanied by administration of carbidopa and 5‐HTP, LH pulse amplitude (2.32 ± 0.71 IU/l) did not differ significantly from its value in either the GnRH + carbidopa phase (2.58 ± 1.12 IU/l) or the unaccompanied GnRH phase (2.77 ± 1.76 IU/l).CONCLUSIONS L‐5‐hydroxytryptophan‐induced amplification of LH secretion in humans is not due to enhancement of the pituitary response to GnRH. The effect of L‐5‐hydroxytryptophan must therefore be due to its action on the hypothalamus, where it may be hypothesized that it increases GnRH release.
Hypokalaemia during insulin‐induced hypoglycaemia in hypopituitary adults with and without growth hormone deficiency
Authors: Davies J. S. , Hinds N. P. , Millward E. M. , McDowell I. , Scanlon M. F. 
Published: March 2003

OBJECTIVEWe have investigated plasma potassium changes during insulin‐induced hypoglycaemia (IIH) in adult patients with growth hormone deficiency (GHD) who have low total body potassium and may also have a vulnerable myocardium due to an increased prevalence of atherosclerosis.DESIGNHypoglycaemia was induced through the administration of intravenous soluble insulin (0.1 U/Kg, IV).SUBJECTS23 consecutive adult patients undergoing routine biochemical evaluation for hypopituitarism.MEASUREMENTSGH, cortisol glucose, sodium and potassium levels were measured at 0, 30, 60, 90 and 120 min after insulin administration. Pituitary function was also assessed through measurement of TSH, thyroid hormones, LH/FSH, testosterone and 17‐oestradiol. IGF‐I concentrations were also analysed.RESULTSAll patients achieved adequate hypoglycaemia (nadir glucose < 2 mmol/l). 15 patients had GHD (peak GH < 10 mU/l) either in isolation or as part of a spectrum of pituitary hormone deficiencies. The remaining 8 patients had normal pituitary function. Plasma potassium concentrations (mean ± SEM) fell from 3.8 ± 0.3 mmol/l (normals) and 3.8 ± 0.2 mmol/l (GHDs) to nadir concentrations of 3.0 ± 0.2 mmol/l and 3.1 ± 0.3 mmol/l, respectively (P < 0.005). Overt hypokalaemia (< 3.5 mmol/l) occurred in 13/15 GHDs and all normals. There were no significant differences between the groups.CONCLUSIONSInsulin‐induced hypoglycaemia causes similar degrees of significant hypokalaemia in patients with normal pituitary function and in those with GH deficiency, either alone or in combination with other pituitary hormone deficiencies. Therefore, insulin‐induced hypoglycaemia does not appear to be associated with any greater risk of hypokalaemia in hypopituitary adults with GHD compared to those with normal anterior pituitary function.