bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymphocytic traffic and homing into target tissue and the generation of endocrine autoimmunity
Authors: Pozzilli P. , Carotenuto P. , Delltala G.
Published: March 2008

Endocrine autoimmunity is known to be characterized by the presence of specific autoantibodies and from the histopathological point of view by lymphocytic inflitration in the target tissue. The presence of mononuclear cell infiltrates is the pathological hallmark of most endocrine diseases characterized by an autoimmune process directed against antigens expressed on endocrine cells. Infiltrating cells can usually be detected by biopsy or by using other, non‐invasive, techniques. However, in endocrine tissue such as the islets of Langerhans and the adrenal glands it is difficult to perform biopsies and diagnosis of the autoimmune process is dependent mainly upon detection of specific autoantibodies. A crucial aspect of endocrine autoimmunity and of all processes of organ specific autoimmunity is why and how lymphocytes migrate from primary lymphoid tissue to their specific targets. This occurs mainly through contact with specific adhesion molecules which enable lymphocytes to adhere to the endothelial vessels. In close proximity to the target tissue. In this review we discuss the homing of peripheral mononuclear cells into target endocrine tissues and the mediating role of adhesion molecules.
Ovarian stromal hypertrophy in hyperandrogenic women
Authors: Dewailly Didler , Robert Yann , Helln Isabelle , Ardaens Yves , Thomas‐Desrousseaux Patricla , Lemaltre Laurent , Fossati Plerre
Published: March 2008

OBJECTIVE By using vaginal endosonography, ovarian stromal hypertrophy has been shown to be a strong diagnostic feature of polycystic ovarian syndrome and related states. However, this sign is difficult to quantify and to correlate with other findings because of its subjectivity. We have evaluated the use of computer assisted analysis of ultrasound scans to provide more objective measurements of ovarian structure and size.

DESIGN We used a computer assisted method for the reading of ultrasound scans. It allowed selective calculation of the stromal area by subtraction of the cyst area from the total ovarian area on a longitudinal ovarian section.

PATIENTS A consecutive series of 57 patients with hyper‐androgenism (group 1), 17 patients with hypothalamic anovulation (group 2) and 20 normal women (group 3).

RESULTS By computerized measure, 75% patients from group 1 had a bilateral stromal area above the mean +2 SD (700 mm2) of women from group 3. All patients from group 2 were below this threshold. Serum LH level was above the normal range in 45% patients from group 1. The stromal area correlated positively with the serum A4‐androstenedione (r= 047, P < 0.005) and 17α‐hydroxy‐progesterone (r= 039, P < 0.005) levels, exclusively in group 1. It did not correlate with the basal serum testosterone, LH or Insulin levels. The cyst area did not correlate with any hormonal parameter.

CONCLUSION Ovarian stromal hypertrophy is a frequent and specific feature of hyperandrogenism. It correlates with the ovarian androgenic dysfunction. Its presence is not always linked with elevated serum Immunoreactive LH levels. Further data are needed to elucidate the role of insulin and ovarian growth factors.
Androgen suppressive effect of GnRH agonist in ovarian hyperthecosis and virilizing turnours*
Authors: Pascale Mirae‐Mirakian , Pugeat Michel , Roberts Marc , Rousset Hugues , Déchaud Hanri , Dutrleux‐Berger Nicole , Tourniaire Jacques
Published: March 2008

OBJECTIVE Recent studies have suggested that androgen secretion by ovarian virllizing tumours may be gonadotrophin dependent. The aim of this study was to investigate the suppressive effect of GnRH agonist administration on androgen secretion. In women with such tumours.

DESIGN AND PATIENTS A single 1.m. Injection Of D‐Trp‐6‐GnRH (GnRHa), 3·75 mg, was given to five unrelated patients referred for clinical symptoms of virilization with plasma testosterone (T) levels greater than 7 nmol/l but with normal dehydroeplandrosterone sulphate (DHEAS) levels. Diagnoses of adrenal tumour or a non‐classical 21‐hydroxylase deficiency were screened for by the dexamethasone suppression test, ACTH stimulation test and adrenal CT scanning, and were ruled out in all patients. The one premenopausal patient received cyproterone acetate in a dose of 50 mg twice dally for 3 weeks, starting 1 week before GnRHa administration.

MEASUREMENT Testosterone, androstenedione (A), DHEAS, 17‐hydroxyprogesterone (OHP), LH and FSH plasma concentrations were measured by radioimmunoassay of blood samples taken before and 3 weeks after GnRHa.

RESULTS In each patient, GnRHa suppressed gonadotrophin levels and reduced T and A to the range for normal control women. With these results, and because accurate localization of an ovarian androgen secreting tumour could not be achieved by pelvic ultrasonography and CT scanning, exploratory laparotomy was undertaken. A Sertoll‐Leydig cell tumour was found in the premenopausal patient, and granulosa cell tumour, hllus cell tumour and two hyperthecoses in the four post‐menopausal patients. After bilateral ovarlectomy and hysterectomy in the post‐menopausal woman and after unilateral ovarlectomy in the premenopausal women, androgen levels were normalized.

CONCLUSIONS In virllized women, the findings of Increased serum testosterone with normal gonadotrophin levels and GnRHa suppression of gonadotrophins leading to normalization of testosterone levels, suggest that various ovarlan androgen‐secreting tumours, as well as hyperthecosis, are not autonomous but apparently depend upon continuous gonadotrophin stimulation.
Two mutations causing vitamin D resistant rickets: modelling on the basis of steroid hormone receptor DNA‐binding domain crystal structures
Authors: Rut A. R. , Hewlson Y. , Kristjansson K. , Luisl B. , Hughes M. R. , O'Riordan J. L. H.
Published: March 2008

OBJECTIVE Hereditary vitamin D resistant rickets (HVDRR) has been shown to be due to mutations in the gene encoding the vitamin D receptor (VDR). In two patients with the characteristic phenotype we have investigated the functional defect and sequenced the VDR cDNA. We report two new mutations in the DNA binding domain of the VDR gene and we have used the crystal‐lographic structure of the glucocorticold and oeltrogen receptors (GR and ER respectively) as models to explain the stereochemical consequences of these mutations.

DESIGN Patient and control cell lines prepared from skin fibroblasts were used to measure binding of 1,25dlhydroxyvltamln D3 (1,25(OH)2D3) and functional responses to this hormone. These cells were also used to Isolate VDR mRNA from which cDNA was prepared and sequenced. VDR cDNA from affected and control patlents was also transfected into receptor defective cells to analyse further functional responses to 1,25(OH)2D3. Computer analysis of mutations in the VDR gene was carried out using the glucocorticold and oestrogen receptors as model systems.

PATIENTS Two patients with HVDRR from unrelated families.

MEASUREMENTS Cytosollc binding and nuclear association of 1,25(OH)2D3 were determined in control and affected patients, and functional response to 1,25(OH)2D3 was assessed by measurement of 2bhydroxyvltamln D‐24‐hydroxylase activity (24‐hydroxylase). VDR cDNA was sequenced and transfected into VDR‐deficient CV‐1 cells for further analysis of functional response to 1,25(OH)2D3 following cotransfection with a chloramphenicol acetyltransferase (CAT) reporter plasmid.

RESULTS Cells from HVDRR patients I and II showed detectable numbers of VDR with normal hormone binding. However, unlike controls, the HVDRR cells did not show induction of 24‐hydroxylase activity following treatment with 1,25(OH)2D3. Sequencing of cDNA revealed single mutations, in patient I (Phe44 → IIe) and in patient II (Lys42 → Glu). Both these residues are conserved in the steroid/thyroid hormone receptor superfamily and stereochemical analysis has been used to deduce the importance of these amino acids and the deleterious effect of these and other mutations in the DNA‐binding domain of the VDR.

CONCLUSIONS Two new mutations in the vitamin D receptor which cause hereditary vitamin D resistant rickets have been described and using molecular modelling we have been able to analyse the genesis of this inherited disease at the level of stereochemistry.
IGF‐I treatment of adult patients with Laron syndrome: preliminary results
Authors: Laron Zvi , Klinger Beatrice
Published: March 2008

OBJECTIVE Laron syndrome is a genetic disease due to a defect in the GH receptor or in the pod‐receptor mechanism which leads to an inability to generate IGF‐I. Biosynthetic IGF‐I treatment given to dwarfed children with this syndrome, produced a significant acceleration of growth velocity and reduction in obesity. In view of the known metabolic disturbances in untreated adult patients, the present clinical trial was performed to define the usefulness of IGF‐I treatment in LS adults.

PATIENTS AND DESIGN Five patients (1 male, 4 females) aged 28‐40 years were treated during 9 months by daily administration of IGF‐I (120 μg/kg), and followed for 6 months after its discontinuation.

METHODS At each visit, a complete physical examination was performed and blood was drawn for biochemical and hormone determinations. Twenty‐four‐hour urinary samples were collected at various Intervals during treatment. Bone densitometry was performed before and after 6‐9 months of therapy.

RESULTS The main findings were a reduction in subscapular skinfold thickness (from 27·5 ± 1·4 (mean ± SEM) to 19·5 ± 1·0 mm; P < 0·002), a decrease in total cholesterol (from 6·78 ± 0·28 (mean ± SEM) to 5·80 ± 0·36 mmol/l) and in LDL cholesterol (from 4·86 ± 0·23 to 3·76 ± 0·35 mmol/l), an increase in creatlnlne clearance (from 71·2 ± 8·4 to 86·8 ± 4·3 ml/min/l·73m2, P < 0·04), an increase in phosphate reabsorption (from 0·89 ± 0·06 to 1·14 ± 0·06 mmol%; P < 0·02) leading to an increase in serum phosphate (from 1·08 ± 0·06 to 1·27 ± 0·03 mmol/l; P < 0·03), a rise in alkaline phosphatase (from 80·8 ± 5·0 to 100·7 ± 7·0 U/I) and in procollagen I‐PICP (from 44·2 ± 4·0 to 171·0 ± 19·2 μg/l; P < 0·0001) and in procoilagen III‐PIIINP (from 2·68 ± 0·45 to 10·10 ± 1·4μg/l; P < 0.005). There was a transient retention of water, sodium and chloride. Pretreatment serum IGFBP‐3 levels were low, but increased progressively during treatment. This permitted a reduction in the IGF‐I dose. There were no adverse effects other than pain and slight erythema at the injection site during the first weeks of treatment. All the anthropometric and metabolic changes reversed upon discontinuation of IGF‐I.

CONCLUSIONS IGF‐I treatment is beneficial in adults, as well as in children, with resistance to GH.
An audit of selected patients with non‐functioning pituitary adenoma treated by transsphenoidal surgery without irradiation
Authors: Bradley K. M. , Adams C. B. T. , Potter C. P. S. , Wheeler D. W. , Anslow P. J. , Burke C. W.
Published: March 2008

OBJECTIVE To determine whether the rate of tumour regrowth in patients with non‐functioning pituitary tumour treated by transsphenoidal surgery and selected for observation without post‐operative irradiation is acceptably low, and to identify a group of patients who could appropriately avoid pituitary irradiation.

SUBJECTS One hundred and thirty‐two patients treated by transsphenoidal surgery, of whom 98 did not undergo post‐operative irradiation. These 98 were selected as having had apparently complete surgical removal, and as lacking features of tumour invasion or rapid growth; 73 of them are being followed by serial pituitary imaging to detect tumour regrowth.

RESULTS Forty‐two patients who have been imaged on two or more occasions or more than two years after operation have shown no sign of tumour regrowth; 25 of them have been imaged at 3 or more years after operation, 13 at more than 5 years, and 4 at more than 10 years. Eight patients have shown regrowth as judged by imaging, although only one had pressure symptoms at the time; 5 out of 6 of these recurrences were found within 5 years of operation (two cannot be timed). The unirradiated group of 73 patients showed 90% recurrence‐free survival at 5 years (95% confidence limits 80‐100%).

CONCLUSIONS Provided that careful surgery and meticulous recall mechanisms for imaging can be ensured, patients so selected may be given the information contained in these results and offered the choice of follow‐up by imaging alone, without pre‐emptive irradiation. We recommend that they should be imaged 6‐8 weeks post‐operatively, then at either 6 or 12 months depending on the appearance, and then every 3‐5 years for at least 15 years. By this means, many patient‐years of good health and relative medical independence can be gained, together with some financial saving.
Evidence for the effect of antibodies to TSH receptors on the thyroid ultrasonographic volume in patients with Graves' disease
Authors: Rieu Max , Raynaud Agathe , Richard Alain , Lapianche Sophie , Sambor Boris , Berrod Jean‐Louis
Published: March 2008

OBJECTIVE it has been demonstrated that antibodies (Ab) to thyroid‐stimulating hormone receptors (R), which stimulate the thyroid gland, induce hyperthyroidism in patients with Graves' disease. Furthermore, it has been shown in thyroid cells in culture that thyroid‐stimulating hormone receptor Ab acts through the adenosine 3′, 5′‐monophosphate pathway which stimulates both thyroid hormonogenesis and growth. We investigated the relations between thyroid autoimmunlty expression and thyroid ultrasonographic parameters or thyroid hormonal status in patients with Graves' disease.

PATIENTS A prospective study of 53 consecutive patients referred with untreated Graves' disease.

MEASUREMENTS Measurements were made of serum TSH‐R, peroxidase (TPO) and thyroglobulin (Tg) Ab and basal plasma free T4 (FT4), free T3 (FT3) and TSH. Thyroid morphological characteristics (number and total volume of nodule(s), total volume of lobes and total thyroid volume) were determined by ultrasonography.

RESULTS There were significant correlations (P < 0·001) between TSH‐RAb levels and FT4 values (r= 0·48) or FT3 levels (r= 0·46). Likewise, significant correlations were found between TSH‐RAb levels and total lobe volume values (r= 0·56, P < 0·001), total nodular volume values (r= 0·59, P < 0·01) or total thyroid volume values (r= 0·63, P< 0·001). By contrast, no correlation was found between TSH‐RAb levels and the number of nodules or between any of the ultrasonographic parameters and TPOAb levels or TgAB values.

CONCLUSIONS This study demonstrates, in vivo, that TSH receptor antibodies modulate the thyroid ultrasonographic edranodular and nodular volumes in patients with Graves' disease.
Corticotrophin‐releasing factor immunostaining is present in placenta and fetal membranes from the first trimester onwards and is not affected by labour or administration of mifepristone
Authors: Cooper E. S. , Brooks A. N. , Miller M. R. , Greer I. A.
Published: March 2008

BACKGROUND AND OBJECTIVES Corticotrophin releasing factor (CRF) is present in the human placenta and fetal membranes. Placental CRF content and plasma CRF concentrations rise throughout gestation and fail rapidly after delivery. The regulation of CRF production from the placenta is poorly understood. The objective of this study was to use the antiprogestin, mifepristone, to determine whether progesterone has a regulatory effect on CRF production in the first trimester of pregnancy.

PATIENTS Women undergoing first trimester (gestation 5‐12 weeks) therapeutic abortion (by suction curettage with and without the synthetic PGE, analogue, gemeprost (16,16‐dimethyl‐trans‐ Δ2‐PGE1 methyl ester) vaginally 2‐4 hours prior to the procedure; or with 600 mg mifepristone 48 hours prior to receiving 1 mg gemeprost vaginally), second trimester therapeutic abortion (600 mg mifepristone, 1 mg gemeprost), In association with pre‐term delivery (gestation 25‐34 weeks) and at term (gestation 35‐42 weeks) by spontaneous delivery, induced labour or elective Caesarean section.

MEASUREMENTS immunohistochemical localization Of CRF and quantification of CRF content by radioimmunoassay of tissue extracts, in human placenta and fetal membranes.

RESULTS CRF was Immunolocalized to the syncytlo‐trophoblast cells of the placenta at ail stages of gestation from 5 to 42 weeks. In the fetal membranes CRF immunoreactlvity was localized in the epithelial and subepithelial cells of the amnion, some cells of the reticular and cellular layers of the chorion, and in decidual stroma. This pattern was seen in all tissues studied. Pretreatment with prostaglandins, mifepristone or both during the first trimester did not alter the distribution or the intensity of the CRF Immunostaining. Placental CRF content rose throughout gestation but, consistent with the Lmmunostaining results, was unaffected by the administration of mifepristone or by labour.

CONCLUSIONS CRF is localized in the syncitlotropho‐blast cells of the placenta and is clearly present early in the first trimester of pregnancy. The lack of an effect of mifepristone or mode of delivery suggests that syncytlo‐trophoblast produces CRF constitutively throughout pregnancy.
Growth hormone deficiency coupled with hypogonadism in AIDS
Authors: Ng Tony T. C. , O'Connell Ian P. M. , Wilkins Edmund O. L.
Published: March 2008

Both growth hormone and sex steroid deficiencies are known to affect quality of life adversely. Hypogonadism is not infrequent in patients with AIDS and due mostly to hypothalamic or end‐organ failure. The prevalence of GH deficiency is unknown. We report two cases of GH deficiency in AIDS, one of which war associated with gonadotroph failure. The significance of GH deficiency in HIV infection in terms of its potential effects on disease progression is discussed. Further studies are required to assess the prevalence of OH deficiency and to clarify its role in the immunopathogenesis of AIDS.
Pyridostigmine induced growth hormone release in mania: focus on the cholinergic/somatostatin system
Authors: Dinan Timothy G. , O'Keane Veronica , Thakore Jogin
Published: March 2008

OBJECTIVE The release of growth hormone (GH) from the anterior pituitary is partly under cholinergic control. Pyridostigmine, the acetylcholinesterase inhibitor, releases GH by this mechanism. Pyridostigmine/GH responses have been reported as enhanced in depression. The aim of the current study was to examine such responses during a manic episode.

DESIGN A between subjects design was employed.

SUBJECTS Seven male manic patients and seven male healthy controls were studied. They were matched in terms of age and body mass index.

MEASUREMENTS GH response to pyridostigmine (120 mg) challenge was measured as the net increase above baseline. Cortisol levels were also measured.

RESULTS Release of GH in the manic patients was significantly enhanced and their baseline Cortisol levels were elevated.

CONCLUSIONS These results demonstrate enhanced pyridostigmine/GH responsiveness in mania which may be due to enhanced somatostin tone or increased cholinergic receptor responsivity.
Influence of sodium valproate on medium‐late luteal phase pulsatile LH secretion in normal women
Authors: Abeal J. Lado , Losada C. Rey , Agricola J. M. Cabezas , Cabezas‐Cerrato J.
Published: March 2008

OBJECTIVE It is not known whether gamma‐aminobutyric acid (GABA) is involved in control of pulsatile LH secretion in human beings. Previous work by our group has shown that manipulation of the GABAergic system with sodium valproate does not affect pulsatile LH secretion in normal women in the late follicular phase. However, it has been suggested that steroid levels are critical for the influence of GABA upon hormone secretion; in particular, progesterone has been said to enhance inhibition by GABA. In this work we studied the effect of sodium valproate on pulsatile LH secretion in medium‐late luteal phase of normal women.

DESIGN Six normal young women were studied over an 8‐hour period in two successive menstrual cycles. On each occasion blood samples were taken every 10 minutes between 1000 and 1800 h. We administered 400 mg of sodium valproate every 8 hours on the 7 days preceding their second cycle and additional 400 mg at 0900 and 1400 h on the day of the study. Ovulation day was estimated by means of serial ovarian ultrasound examinations and confirmed by serum progesterone concentrations.

MEASUREMENTS In each cycle, LH, oestradiol and progesterone were determined by radioimmunoassay and sodium valproate by repolarization fluorescence spectrophotometry. The series of LH levels was smoothed for 1‐minute sampling periods by means of a spline function and analysed by means of a program developed in our laboratory and written in Fortran 77. The program deconvolved the signal and calculated the pulse area, pulse duration, interpulse interval and number of pulses. LH pulse identification on the deconvolved signals was performed using our own method based on Friedman's non‐parametric statistic. The statistical significance of differences between parameters was estimated using the Mann‐Whitney test and Wilcoxon signed rank test.

RESULTS There were no significant differences in LH pulse area, pulse duration, interpulse interval or number of pulses with the administration of sodium valproate.

CONCLUSIONS Activation of the GABAergic system with sodium valproate had no biologically significant effect on the mid‐late luteal phase pulsatile LH secretion in normal women.
Acute suppurative thyroiditis in an asymptomatic woman: an atypical presentation simulating thyroid carcinoma
Authors: Yamashita Jun‐ichi , Ogawa Michio , Yamashita Shin‐ichi , Saishoji Telsushi , Nomura Koichi , Tsuruta Jun‐ji
Published: March 2008

Patients with acute suppurative thyroiditis usually have pain or tenderness in the anterior part of the neck associated with erythema and dysphagia. A 26‐year‐old Japanese woman with none of these symptoms presented with a left anterior cervical mass. Since physical examination and laboratory studies showed a firm and irregular tumour located in the left lobe of the thyroid without any inflammatory signs, we made a diagnosis of thyroid carcinoma. After surgery, histological examination of the thyroid specimen revealed various changes of severe inflammation, and a barium swallow demonstrated a left pyriform sinus fistula. We describe here a unique case of acute suppurative thyroiditis in an asymptomatic woman.
Acute effects of a single administration of dexamethasone on basal and growth hormone‐releasing hormone stimulated GH secretion in acromegaly
Authors: Losa Marco , Arosio Maura , Cusin Alberto , Biella Orietta , Palmieri Eva , Faglia Giovanni , Giovanelli Massimo
Published: March 2008

A single administration of dexamethasone causes both an early stimulatory and a late inhibitory effect on GH secretion in normal subjects.

OBJECTIVE We investigated the effects of a single administration of dexamethasone on basal and GH‐releasing hormone‐stimulated GH secretion in eight patients with active acromegaly.

DESIGN On three different days the patients received 4 mg i.v. dexamethasone, 1 μg/kg body weight GH‐releasing hormone 1‐29, or matched placebos in different order.

PATIENTS Eight subjects with active acromegaly, five of whom had not been treated previously, while the other three had received octreotide therapy which was stopped at least 7 days before testing.

MEASUREMENTS Serum GH levels were measured in duplicate by a commercially available RIA kit.

RESULTS Dexamethasone administration caused a significant decline of mean ± SE GH levels from 51.8 ± 13.8 to 30.0 ± 9.2 mU/l at 180 minutes, that was not influenced by placebo administration at 180 minutes. On the contrary, when GH‐releasing hormone substituted placebo administration, GH levels increased from 34.0 ± 9.8 mU/l at 180 minutes to 56.0 ± 15.6 mU/l at 195 minutes. The GH increase was higher when GH‐releasing hormone was given without dexamethasone pretreatment (from 52.4 ± 13.0 mU/l at 180 minutes to 86.4 ± 25.4 mU/l at 195 minutes). Analysis of the GH area under the curve confirmed the significant inhibition of GH secretion after dexamethasone administration and the significant reduction of the GH response to GH‐releasing hormone in the study with dexamethasone pretreatment.

CONCLUSIONS At variance with data in normal subjects, acute i.v. administration of dexamethasone inhibits basal GH secretion and partially suppresses the GH response to GH‐releasing hormone in acromegaly. Both alterations in the regulatory mechanism of adenomatous cells and perturbations of hypothalamic regulatory influences, induced by the state of chronic GH hypersecretion, are likely explanations of the different response to dexamethasone.
In‐vitro evidence for the regulation of 17,20‐lyase activity by cytochrome b5 in adrenocortical adenomas from patients with Cushing's syndrome
Authors: Sakai Yoshiyuki , Yanase Toshihiko , Hara Takayuki , Takayanagi Ryoichi , Haji Masafumi , Nawata Hajime
Published: March 2008

OBJECTIVE The electron transfer system molecules, NADPH‐cytochrome P450 reductase (Red) and cytochrome b5 (bS) are known to increase the relative activity of 17,20‐lyase to 17α‐hydroxylase in vitro. Consistent with this hypothesis, we have reported recently that adrenocortical adenomas from patients with Cushing's syndrome that produced exceptionally high concentrations of androgens also contained more b5 mRNA as well as greater 17,20‐lyase activity than adenomas that produced low concentrations of androgens. This finding was suggestive but inconclusive in linking b5 functionally to this difference in adenoma 17,20‐lyase activity. In the present study, we have extended this finding by examining the effect of bS on microsomal 17,20‐lyase activity using an antibody against cytochrome b5.

DESIGN Biochemical quantitation of the content of b5 and Red activity in the microsomal fraction of the tumours and determination of 17,20‐lyase activity In the microsomes in the presence or absence of an antibody against b5.

PATIENTS Seven patients with a clinical diagnosis of Cushing's syndrome secondary to benign adrenocortical adenoma were studied.

MEASUREMENTS The microsomal activities of 17α‐hydroxylase, 17,20‐lyase and 3β‐hydroxysterold dehydrogenase were measured by in‐vitro enzyme assay with thin layer chromatography. Microsomal Red activity was assayed by measuring NADPH‐dependent cytochrome c reduction reaction. Cytochrome b5 concentration was determined by spectrophotometric analysis.

RESULTS An in‐vitro enzyme assay of microsomal fractions from the adenoma showed that the 17,20‐lyase activities of two adenomas that produced high concentrations of adrenal androgen were threefold greater than those of five other adenomas that produced low concentrations of androgens. Cytochrome b5 concentrations were greater in the two adenomas with high 17,20‐lyase activity than in the other adenomas, while no significant difference in Red activity was observed among all the adenomas. The increased 17,20‐lyase activity in the two adenomas was partially but significantly antagonized by an antibody against b5.

CONCLUSIONS These results suggest that differences in tissue b5 are functionally associated with differences in 17,20‐lyase activity in adrenocortical adenomas In Cushing's syndrome, resulting in a dissociated secretion of Cortisol and androgens in some patients.
Doppler echocardiographic evaluation of left ventricular diastolic function in acute hypothyroidism
Authors: Grossmann Georg , Wieshammer Siegfried , Keck Fritz S. , Göller Veit , Giesler Martin , Hombach Vinzenz
Published: March 2008

OBJECTIVE Left ventricular diastolic dysfunction Is an important cause of symptomatic heart failure. Previous studies suggest that thyroid dysfunction affects left ventricular diastolic function but the underlying mechanisms remain controversial. The study was undertaken to assess the influence of acute hypothyroidism on left ventricular diastolic function and to elucidate possible underlying mechanisms by means of Doppler echocardiography in a group of athyreotic patients, whose thyroid state depended only on external thyroid hormone supply and could therefore easily be controlled.

PATIENTS Eleven patients (5 men, 6 women, aged 20‐55 years), who had had total thyroidectomy, were investigated during mild hyperthyroidism and during acute hypothyroidism. Additionally, 11 healthy control subjects aged 25‐51 years were included in the study.

DESIGN M‐mode echocardiography of the left ventricle and pulsed‐wave Doppler echocardiography of the trans‐mitral flow velocity pattern were carried out.

RESULTS Acute hypothyroidism produced a decrease of left ventricular end‐diastolic diameter from 48 ± 5 to 46 ± 5 mm (mean ± SD P < 0.05), of peak velocity of early diastolic filling from 0.52 ± 0.10 to 0.42 ± 0.05 m/s (P < 0.05), of peak velocity of late diastolic filling from 0.42 ± 0.10 to 0.36 ± 0.09 m/s (P < 0.05), and a decreased time‐velocity integral of early diastolic filling (6 2 ± 1 8 vs 5.1 ± 0.7 cm, P < 0.05). The other M‐mode and Doppler echocardiographic parameters did not differ between the hyperthyroid and the hypothyroid states.

CONCLUSIONS The observed changes of the transmitral flow velocity pattern during acute hypothyroidism can be attributed to a reduction of pre‐load. There is no direct evidence that acute hypothyroidism affects the intrinsic diastolic properties of the left ventricle.
Sustained suppression of serum LH, FSH and testosterone and increase of high‐density lipoprotein cholesterol by daily injections of the GnRH antagonist cetrorelix over 8 days in normal men
Authors: Behre Hermann M. , Böckers Anja , Schlingheider Annette , Nieschlag Eberhard
Published: March 2008

OBJECTIVE Recently we have shown that single dose injections of the new GnRH antagonist cetrorelix ([Ac‐o‐Nal(2)1, D‐Phe(4CI)2, D‐Pal(3)3, D‐Cit5, D‐Ala10]GnRH; SB‐75) decrease serum LH and testosterone in a dose‐dependent manner in normal men. These results prompted us to investigate the effectiveness and safety of multiple daily injections of cetrorelix in normal male volunteers.

DESIGN AND VOLUNTEERS Following two control examinations 16 young men were randomly assigned to four study groups (n= 4/group). Daily doses of 0 (placebo), 2, S, and 10 mg cetrorelix were injected subcutaneously at 0800 h for 8 days and morning and evening blood samples were obtained for 3 weeks.

RESULTS One day after the first cetrorelix injection, serum LH and testosterone concentrations were significantly suppressed in all treatment groups. Whereas in the 2 and 5‐mg dose groups LH and testosterone showed some fluctuations, daily injections of 10 mg cetrorelix consistently suppressed LH and testosterone in all men. In addition, in this group serum FSH concentrations were significantly suppressed to subnormal values 1 day after the first injection and remained in this range up to 5 days after the last injection. A time and dose‐dependent increase of high‐density lipoprotein cholesterol was observed during cetrorelix‐induced testosterone deprivation with a maximal increase of 0 38*013 mmol/l (14 8 ±5 1 mg/dl; mean ±SEM) in the 10‐mg dose group. In addition, parallel to suppressed testosterone the volunteers' libido was significantly reduced under the GnRH antagonist. Apart from those symptoms caused by androgen deficiency, the only adverse side‐effect observed was a mild painless local erythema at the injection site that disappeared within an hour.

CONCLUSIONS Daily injections of 10 mg cetrorelix effectively and consistently suppress serum LH, FSH and testosterone concentrations, and therefore it has potential for treatment of sex hormone‐dependent diseases and for male contraception.
Longitudinal study of maternal plasma bioavailable testosterone and androstanediol glucuronide levels during pregnancy
Authors: Kerlan Véronique , Nahoul Khalil , Le Martelot Marie‐Thérèse , Bercovici Jean‐Pierre
Published: March 2008

OBJECTIVE The aim of this study to evaluate during normal pregnancy plasma bioavailable testosterone and androstanediol glucuronide levels.

MEASUREMENTS Bioavailable testosterone, androstanediol glucuronide and SHBG levels were evaluated every 4 weeks from week 6 to week 38 in 10 normal pregnant women. We also measured plasma oestradiol, oestriol, Δ4‐androstenedione, 17‐hydroxyprogesterone, progesterone and testosterone.

RESULTS The mean bioavailable testosterone levels were within the range of non‐pregnant women but with an increasing trend until delivery. Androstanediol glucuronide had increased at weeks 6 and 8, decreased at week 14, remained low at week 30, and increased again at week 34. SHBG was significantly correlated with testosterone, oestradiol and oestriol. No correlation could be established between androstanediol glucuronide and any other parameter.

DISCUSSION Bioavailable testosterone (non‐SHBG bound testosterone) represents the sum of free testosterone plus albumin bound testosterone. The increase in testosterone concentrations with decreased albumin levels during pregnancy, could suggest reduced metabolic clearance of testosterone throughout pregnancy. No correlation was established between the decrease in androstanediol glucuronide and increase in progesterone, suggesting that the decrease in androstanediol glucuronide is not a consequence of the inhibitory effect of progesterone on 5α‐reductase activity.
Assessment of 5α‐reductase activity in hirsute women: comparison of serum androstanediol glucuronide with urinary androsterone and aetiocholanolone excretion
Authors: Gilad S. , Chayen R. , Tordjman K. , Kisch E. , Stern N.
Published: March 2008

OBJECTIVE Recent evidence suggests that androstanediol glucuronide (AG), a metabolite of dihydrotestosterone (DHT) formed in skin, is frequently elevated in hirsute women, presumably reflecting enhanced 5a‐reductase activity. An alternative method of demonstrating 5a‐reductase activity is the androsterone (A)/aetiocholano‐lone (E) ratio in urine. A and E are the 5α‐ and 5β‐ reduced metabolites, respectively, of androstenedione, which is the principal metabolite of dehydroepiandrosterone (D). Although serum AG and the urinary A/E ratio have both been considered valid methods for assessing 5α‐reductase activity, the two have not been previously compared in hirsute women. The present study was undertaken to assess 5a‐reductase activity in hirsute patients as determined by these two different methods.

PATIENTS AND MEASUREMENTS We surveyed 47 untreated women (ages 17–33) with various degrees of hirsutism. Serum testosterone, bioavailable testosterone, dehydroepiandrosterone sulphate, and AG were determined. Additionally, A, E and D were measured in 24‐hour collections of urine.

RESULTS For the 47 women, 37 had elevated blood levels of AG (17.4 ± 2.2, mean±SEM; normal <8 nmol/l), but only 18 of these had an increased urinary A/E ratio (> 1.5). All but one of the remainder had elevated urinary and/or serum androgen levels. Overall, no significant correlation between AG and A/E was observed. There was a highly significant correlation between AG in serum and A in urine (r= 0.82, P<0 001). AG was also positively related to dehydroepiandrosterone sulphate (r= 0.64; P< 0.005), bioavailable testosterone (r= 0.6; P<0001), aetiocholanolone (r= 0.58; P<0 001) and total testosterone (r= 0.52; P& 0.01). In contrast, A/E was not significantly related to androgen production.

CONCLUSIONS There is a poor correlation between AG and the A/E ratio in hirsute women. Although AG may be raised by increased 5α‐reductase activity, it is probably also affected by the presence of elevated androgens regardless of 5α‐reductase activity.
Clonal analysis of human adrenocortical carcinomas and secreting adenomas
Authors: Gicquel Christine , Leblond‐Francillard Marie , Bertagna Xavier , Louvel Albert , Chapuls Yves , Luton Jean‐Pierre , Girard François , Le Bouc Yves
Published: March 2008

OBJECTIVES Adrenocortical tumours in man are characterized mainly on biochemical, anatomical and histological grounds which establish their secretory pattern and, with some uncertainty, their benign or malignant nature. To study further these tumours and eventually to shed some light on their pathogenesis, we determined their clonal composition.

METHODS Clonal composition was determined by X‐chromosome inactivation analysis on tumour and leucocyte DNA using three markers: M27β, phosphoglycero‐kinase (PGK) and hypoxanthine‐phosphoribosyl transferase (HPRT) with 88, 33 and 27% heterozygosity rates respectively.

PATIENTS Clonal analysis was performed on 25 tumours from 19 heterozygous female patients: four had a carcinoma, 14 had a single secreting adenoma, and one had autonomous bilateral macronodular hyperplasia with Cushing's syndrome (seven adenomas examined).

RESULTS The malignant tumours had patterns indicative of monoclonality. The single adenomas displayed contrasting results with patterns indicative of monoclonality in eight cases, and patterns indicative of polyclonality in six cases; monoclonal adenomas were larger and had a higher prevalence of nuclear pleomorphism than the apparently polyclonal adenomas. In the patient with bilateral macronodular hyperplasia, different clonal patterns were present in different adenomas: whereas a clear monoclonal pattern was observed in the three adenomas of the right gland, in which the active X‐allele was not always the same, in two interpretable adenomas of the left gland, a moderately skewed pattern suggested a partial monoclonal component.

CONCLUSIONS These data show that adrenocortical carcinomas are monoclonal and suggest that adenomas may arise from a single cell or from more than one cell under the putative action of local growth factors. In adenomas, which until now had appeared homogeneous, this genetic heterogeneity may reflect different pathophysiological mechanisms or it may represent different stages of a common multistep process exceptionally occurring in a single patient with bilateral macronodular hyperplasia.
Effect of hyperinsulinaemia on the function of the pituitary‐adrenal axis in healthy man
Authors: Walker M. , Berrish T. S. , James A. R. , Alberti K. G. M. M.
Published: March 2008

OBJECTIVE Circulating insulin levels in themselves have been reported to influence the counter‐regulatory hormone response to hypoglycaemia in man. The effect of insulin on a specific aspect of this response was examined during euglycaemia by stimulating the pituitary‐adrenal axis with human corticotrophin‐releasing hormone (CRH).

SUBJECTS Eight healthy males.

DESIGN Following an overnight fast, insulin was infused at 15 (low) and 60 (high) mU/kg/h from 0900 h for 180 minutes on separate occasions in random order. On each occasion, blood glucose was clamped at euglycaemia, and 1 μ/kg/kg (i.v. bolus) human CRH was administered at 120 minutes.

MEASUREMENTS Circulating hormone concentrations were determined by radioimmunoassay. Peak Cortisol and ACTH responses were compared for the two study conditions.

RESULTS Mean serum insulin levels were threefold higher during the high compared with the low insulin infusion (mean difference 320 pmol/l, 95% confidence interval (CI) 150‐490, P<0001). Blood glucose levels during the clamps were comparable (mean difference 0 15 mmol/l, 95% CI 0‐0.63). Plasma Cortisol levels increased following CRH, although the peak concentration was significantly lower during the high insulin infusion (mean difference 36 nmol/l, CI 0‐110, P< 0.02). However, peak ACTH levels were comparable for the two insulin levels (mean difference 8 ng/l (1.8 pmol/l), CI 0‐50).

CONCLUSIONS The peak Cortisol response to CRH was diminished at the higher circulating insulin levels. This was not dependent upon concurrent hypoglycaemia and did not appear to be mediated at the level of the pituitary gland.
Serum growth hormone (GH) profiles after nasally administered GH in normal subjects and GH deficient patients
Authors: Maller Jens , Lauersen Torben , Mindeholm Linda , Hoelgaard Annie , Ovesen Per , Jørgensen Jens O. L. , Christiansen Jens S.
Published: March 2008

OBJECTIVE GH‐deficient patients are at present treated with daily subcutaneous GH injections. Further improvements in patient compliance and effects of treatment may occur with nasal administration. We have examined the absorption of nasally administered GH in healthy subjects and In GH deficient patients in two separate studies.

DESIGN Healthy subjects and GH deficient patient were examined in the morning after an overnight fast. Twelve IU of GH in a powder containing didecanoyl‐l‐α‐phosphatidylcholine as enhancer were administered in the nostrils (6 IU in each nostril) at the beginning of the study in the healthy subjects. The GH deficient subjects received a total of 6 IU GH/m2 intranasally. Blood was frequently sampled for up to 4 hours. Before and after nasal application anterior rhinoscopy was performed.

PATIENTS Eight normal subjects and 7 GH deficient patients.

MEASUREMENTS Serum GH.

RESULTS (mean ± SD) Mean maximum concentration (Cmax) in the normal group was 57.6 mU/l ± 36.9 with a mean time to obtain Cmax(Tmax) of 65 ± 47 min. In the GH deficient group Cmax was 56.1 ± 26.1 mU/l with a mean Tmax of 45 ± 15 min. The subjects did not report any major inconvenience during the study. Anterior rhinoscopy did not reveal changes.

CONCLUSION Nasally administered GH is absorbed to a significant degree from the nasal mucosa without obvious untoward effects in the short term. These data encourage further studies with nasal GH administration.
Gynaecomastia caused by a primary mediastinal seminoma
Authors: Nagi Dinesh K. , Jones William G. , Belchetz Paul E.
Published: March 2008

The case of a young man aged 26 is reported. He presented with a short history of painful gynaecomastia, and no other associated symptoms. Radiological investigations showed a mass in the anterior mediastinum. Endocrine investigations showed high circulating oestradiol and high hCG‐β levels. There was no evidence of primary testicular tumour or metastases. Surgical removal of the mediastinal mass led to normalization of oestradiol and hCG‐β levels and regression of gynaecomastia. Histology showed the tumour to be a primary mediastinal seminoma staining positively for hCG‐β Further treatment consisted of chemotherapy with etoposide and cis‐platinum. The patient has remained well with no evidence of disease recurrence. The tumour markers remain normal.
Acute overdose of a new dopamine agonist, CV 205‐502
Authors: Tauveron Igor , Gesta Jean‐Michel , Jalenques Isabelle , Thiebiot Philippe
Published: March 2008

CV 205‐502 is a new dopamine agonist used for hyperprolactinaemia. We report a case of acute overdose (one month treatment, i.e. 2.25 mg) in a 25‐year‐old male patient. Clinical symptoms were restricted to nausea and mild hypotension. Treatment consisting of ipeca cuanha, charcoal and intravenous fluids allowed a rapid, successful outcome. This case illustrates the particular features of CV 205‐502 intoxication when compared to other dopamine agonists, pointing out the tolerance of the drug which can be considered for wider indications and safer prescriptions.
Lithium associated thyrotoxicosis: a report of 14 cases, with statistical analysis of incidence
Authors: Barclay Murray L. , Brownlie Bevan E. W. , Turner John G. , Wells J. Elisabeth
Published: March 2008

OBJECTIVE Lithium is known to cause goitre and hypothyroidism, and has been associated less commonly with hyperthyroidism. We report a series of 14 patients with lithium associated thyrotoxicosis (LiAT), and have used epidemiological data to assess the association between long‐term lithium treatment and the development of thyrotoxicosis.

DESIGN Information for this retrospective study was obtained from records of patients attending the thyroid clinic between 1973 and 1991. Statistical analysis of the association between long‐term lithium treatment and incidence of thyrotoxicosis was made using local thyrotoxicosis incidence figures and lithium prescription data. MEASUREMENTS Investigations included 99mTc pertechnetate thyroid scans, and blood analyses to measure serum T4, serum T3, free T4 index, and thyroid microsomal and thyroglobulin antibody litres.

RESULTS During the 18‐year period there were 14 patients with LiAT. This number of cases of thyrotoxicosis occurring in patients on lithium was more than three times greater than that predicted from local thyrotoxicosis incidence rates (P< 0.05). Scintiscans were obtained for 13 patients: 8 had toxic diffuse goitre, 2 toxic multinodular goitre, 1 toxic uninodular goitre, and 2 had a lack of visualization consistent with ‘painless thyroiditis'. Nine patients received a course of carbimazole and 6 of these remain in remission. Six patients have received 131I therapy. Eight patients have become hypothyroid at follow‐up (5 post 131I, 1 following a course of carbimazole, and the 2 with ‘painless thyroiditis').

CONCLUSIONS Statistical analysis has shown that long‐term lithium therapy is associated with an increased risk of thyrotoxicosis. LiAT is a heterogeneous condition with differing underlying thyroid pathologies and the mechanisms remain uncertain. The management of LiAT should initially be with antithyroid medication, and 131I therapy should be given only to patients who do not obtain long‐term remission.
The iodide perchlorate discharge test in women with previous post‐partum thyroiditis: relationship to sonographic appearance and thyroid function
Authors: Creagh F. M. , Parkes A. B. , Lee A. , Adams H. , Hall R. , Richards C. J. , Lazarus J. H.
Published: March 2008

BACKGROUND Post‐partum thyroid disease occurs in 50% of anti‐thyroid peroxidase (TPO) antibody positive women (detected at 16 weeks' gestation) and is characterized by a transient episode of hyper, hypo or hyper‐hypo thyroidism. In approximately 20% of these women the hypothyroidism is permanent. However, the extent of long‐term thyroid dysfunction, possibly mediated by immune attack, in those anti‐TPO Ab + ve women who have had only transient or no thyroid dysfunction during the postpartum period is not clear.

OBJECTIVE We have therefore studied the frequency of iodide organification defects by iodide perchlorate discharge testing, and of thyroid morphological abnormalities by ultrasound scanning in euthyroid women following their episode of post‐partum thyroiditis (PPT).

DESIGN The study group comprised 17 women with previous PPT (PPT +ve) and 12 women who had positive anti‐TPO antibodies during pregnancy but who did not develop PPT (PPT‐ve). Women were studied 15‐47 months following their episode of PPT.

RESULTS Iodide perchlorate discharge tests were positive (more than 10% discharge) in 7 (41 %) PPT + ve and 5 (42%) PPT‐ve subjects (P = NS). Morphological abnormalities on thyroid ultrasound were detected in 7 of 14 (50%) PPT + ve and 7 of 9 (77%) PPT‐ve subjects (P = NS). There was a strong association between abnormalities of iodide organification and morphology: of 11 subjects with positive iodide perchlorate discharge tests, 10 had abnormal (positive) ultrasound scans; of 12 subjects with negative iodide perchlorate discharge tests 8 had negative ultrasound scans (P= 0.013, Fisher's exact test).

CONCLUSIONS Long‐term subtle defects of thyroid function and morphology are common in women with anti‐TPO antibodies in pregnancy, whether or not they develop postpartum thyroiditis. The clinical significance of these findings is unclear but a continuing thyroid pathological process is suggested.