Showing papers in "Clinical Endocrinology in 2003"

Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study

Abstract: Summary OBJECTIVE To evaluate the impact of maternal hypothyroxinaemia during early gestation (fT4 below the lowest tenth percentile and TSH within the reference range: 0·15‐2·0 mIU/l) on infant development, together with any subsequent changes in fT4 during gestation. DESIGN A prospective 3-year follow-up study of pregnant women and their children up to the age of 2 years. MEASUREMENTS Child development was assessed by means of the Bayley Scales of Infant Development in children of women with hypothyroxinaemia (fT4 below the tenth percentile at 12 weeks’ gestation) at 12 weeks’ gestation (cases), and in children of women with fT4 between the 50th and 90th percentiles at 12 weeks’ gestation, matched for parity and gravidity (controls). Maternal thyroid function (fT4 and TSH) was assessed at 12, 24 and 32 weeks’ gestation. The mental and motor function of 63 cases and 62 controls was compared at the age of 1 year, and of 57 cases and 58 controls at the age of 2 years. RESULTS Children of women with hypothyroxinaemia at 12 weeks’ gestation had delayed mental and motor function compared to controls: 10 index points on the mental scale (95% CI: 4·5‐15 points, P = 0·003) and eight on the motor scale at the age of 1 year (95% CI: 2·3‐12·8 points, P = 0·02), as well as eight index points on the mental (95% CI: 4‐12 points, P = 0·02), and 10 on the motor scale (95%CI: 6‐16 points, P = 0·005) at the age of 2 years. Children of hypothyroxinaemic women in whom the fT4 concentration was increased at 24 and 32 weeks’ gestation had similar scores to controls, while in the controls, the developmental scores were not influenced by further declines in maternal fT4 at 24 and 32 weeks’ gestation. CONCLUSIONS Maternal hypothyroxinaemia during early gestation is an independent determinant of a delay in infant neurodevelopment. However, when fT4 concentrations increase during pregnancy in women who are hypothyroxinaemic during early gestation, infant development appears not to be adversely affected. In the past decade, interest has been rekindled in the relationship between maternal plasma thyroid hormone concentration during pregnancy and subsequent infant neurodevelopment (Pop et al ., 1995, 1999a; Haddow et al ., 1999; Lazarus, 1999; Smit et al ., 2000). It is well known that both maternal thyroid dysfunction during pregnancy (especially hypothyroidism) and severe iodine deficiency adversely affect the outcome of neurodevelopment in children (Delange, 1994; Glinoer, 1997; Mestman, 1999). Even in areas in which there is sufficient iodine intake in the general population, pregnant women often have fT4 plasma levels in the lower ranges, without elevated TSH. This is defined as hypothyroxinaemia, and is generally regarded as a normal condition. However, there is growing concern that hypothyroxinaemia during early gestation could be harmful to the offspring (Pop et al ., 1999b; Utiger, 1999; Morreale de Escobar et al ., 2000). In fact, little is known about maternal fT4 levels during normal pregnancy, or their relationship to the development of the child. This paper describes the results of a longitudinal prospective study that investigates whether maternal thyroid hormone levels, assessed in women without (sub)clinical thyroid function at three different trimesters during pregnancy, are adversely related to child development at 1 and 2 years of age.

Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease

Abstract: Quality thyroid tests are essential for diagnosing and managing thyroid conditions. Indeed, mild (subclinical) hypoand hyperthyroidism are by definition conditions that are recognized by their biochemical profile, typified by an abnormal serum TSH concentration associated with normal range free thyroid hormone (FT4 and FT3) levels. The National Academy of Clinical Biochemistry (NACB) has recently published a consensus monograph entitled Laboratory Medicine Practice Guidelines: Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease that reviews the clinical utility and technical performance of current thyroid tests (Demers & Spencer, 2002). The current scientific literature abounds with articles relating to thyroid conditions, strategies for thyroid testing and the technical performance of different thyroid methodologies. This monograph was prompted by the need to develop a consensus concerning these issues as well as to address the unusual thyroid problems that challenge the diagnostic accuracy of the thyroid tests currently available. These atypical presentations account for a disproportionately large expenditure of laboratory resources to determine the correct diagnosis (Kricka, 2000). In ambulatory patients these unusual presentations include: binding protein abnormalities that affect the diagnostic accuracy of FT4 tests; the presence of thyroglobulin (Tg) autoantibodies that interfere with serum Tg measurements; and medications that compromise the in vivo and in vitro metabolism of thyroid hormones and influence the diagnostic accuracy of TSH measurements. In addition, severe forms of non-thyroidal illnesses (NTI) have a myriad of effects on thyroid test results. This monograph is unique because it contains consensus guidelines that were developed by a process of global review. The review process was initiated at the International Thyroid Congress in Kyoto in October 2000, after which the guidelines were displayed electronically in addition to being distributed to more than 100 thyroid specialists, representing diverse professional associations worldwide, for consensus-building. The information contained in the monograph is presented in discrete chapters. Each chapter covers the clinical utility of a specific test, and contains focused guidelines that describe the physiological strengths and limitations of the test together with its optimal technical performance parameters. Most of the guidelines appeared to have greater than 95% consensus; however, there were some geographically sensitive differences in practice patterns.

Androgens improve cavernous vasodilation and response to sildenafil in patients with erectile dysfunction.

Abstract: Summary objectives We have recently shown that, in men with erectile dysfunction (ED), free testosterone (FT) directly correlates with penile arterial inflow. This led us to further investigate the effect(s) of androgen administration on cavernous arteries in patients failing sildenafil treatment. design Prospective randomized placebo-controlled pilot study. patients Twenty patients with arteriogenic ED as evaluated by dynamic colour duplex ultrasound (D-CDU) studies, normal sexual desire but testosterone (T) and FT in the lower quartile of normal range (low-normal), not responding to sildenafil treatment (100 mg) on six consecutive attempts. measurements All patients had D-CDU, hormonal [LH, prostate-specific antigen (PSA), total and free testosterone, sex hormone-binding protein (SHBG), oestradiol], biochemical [haematocrit, low-density lipoprotein (LDL) and HDL cholesterol, triglycerides], and sexual evaluations [International Index of Erectile Function (IIEF)] before and after 1 month of therapy with transdermal testosterone (5 mg/day, n = 10) or placebo along with sildenafil treatment on demand. Measurement of flow parameters by D-CDU on cavernous arteries was the primary endpoint of the study. Improvement of erectile function was assessed using the IIEF questionnaire and the Global Assessment Question (GAQ). results One month treatment with transdermal testosterone led to a significant increase in T and FT levels (23·7 ± 3·3 SD vs. 12·8 ± 2·1 nmol/l and 473 ± 40·2 vs. 260 ± 18·1 pmol/l, P < 0·01, respectively). In addition testosterone administration induced a significant increase in arterial inflow to cavernous arteries measured by D-CDU (32 ± 3·6 vs. 25·2 ± 4 cm/s, P < 0·05), with no adverse effects. Also, a significant improvement in erectile function domain score at IIEF was found in the androgen but not in the placebo-treated patients (21·8 ± 2·1 vs. 14·4 ± 1·4, P < 0·05) which was associated with significant changes in the GAQ score (80%vs. 10%, P < 0·01). conclusions In patients with arteriogenic ED and low-normal androgen levels, short-term testosterone administration increases T and FT levels and improves the erectile response to sildenafil likely by increasing arterial inflow to the penis during sexual stimulation.

Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index

Abstract: Objective Sensitivity to glucocorticoids differs between individuals, partially due to genetic variation in the glucocorticoid receptor (GR) gene. We studied the sequence alteration of a previously described intronic BclI polymorphism of the GR gene, and investigated whether there was an association with sensitivity to glucocorticoids and anthropometric parameters in a group of healthy elderly individuals. Design and measurements In study group 1, two overnight dexamethasone suppression tests (DSTs) were performed: with 1 mg dexamethasone, and 2.5 years later with 0.25 mg dexamethasone. Anthropometric parameters were measured in a larger population (study group 2), as well as in a third study group, in which we also measured body composition by dual-energy X-ray absorbtiometry (DEXA) scans. Subjects Groups 1 and 2, respectively, 191 and 1963 male and female participants of the Rotterdam study, a population-based study in Dutch elderly. Study group 3: 370 elderly males (mean age 77.8 +/- 0.2 years) from Zoetermeer, the Netherlands. Results We identified the BclI restriction site polymorphism as a C/G substitution in intron 2, 646 nucleotides downstream from exon 2. After both 1 mg and 0.25 mg DST, heterozygous (CG) and homozygous G-allele carriers (GG) had lower cortisol levels than CC-carriers (P = 0.01 and P = 0.02, respectively). In study group 2, we found a lower body mass index (BMI; P = 0.006) and waist-hip ratio (WHR; P = 0.02) in G-allele carriers. In study group 3, again we found a lower BMI (P = 0.05) in G-allele carriers. No differences were found in fat mass. However, lean mass tended to be lower in G-allele carriers (P = 0.07). Conclusions We characterized a BclI-RFLP (restriction fragment length polymorphism) of the GR gene as a C/G polymorphism in intron 2 of which the G-allele was associated with hypersensitivity to glucocorticoids. This resulted in a lower BMI in older individuals in general, while our study in elderly males suggests that the lower BMI is probably due to a greater loss of lean mass during the ageing process.

Long-term outcome and mortality after transsphenoidal adenomectomy for acromegaly.

Abstract: Summary objective Acromegaly has long been associated with increased mortality but few long-term follow-up data are available in patients treated for this disease. We therefore studied a group of 103 patients who underwent transsphenoidal adenomectomy for acromegaly between 1970 and 1999 and were followed for one to 30 years. design and patients A retrospective chart review was performed on 103 patients living in the province of Quebec, Canada. Mortality data were obtained by hospital charts, contact with the patient's family or death certificates. Stringent biochemical criteria were used to define remission (random GH < 2·5 µg/l, or GH nadir after an oral glucose load is < 1 µg/l and IGF-I within the normal range) and patient survival in the group in remission and the group with persistent disease were compared to survival of the population of Quebec, Canada, using the probabilities of the Poisson distribution. results There were four deaths in the perioperative period, one of which was directly related to surgery. Initial remission was obtained in 82% of microadenomas, 60% of macroadenomas and 24% of invasive adenomas. The long-term (≥ 10 years) remission rate for surgery alone was 52%. A second transsphenoidal surgery, radiation therapy and/or octreotide were used in a subset of patients with persistent disease. Long-term remission was obtained in 63% of patients. Five (mean age, 64 years) of the 57 patients in remission died; this rate did not differ significantly from the mortality rate expected in the general population (P = 0·18). Thirteen (mean age, 59·8 years) of the 34 patients with persistent disease died; this rate was significantly higher than that expected in the general population (P = 0·008). conclusions Our observations confirm that uncontrolled acromegaly increases mortality compared to the general population and that mortality rates similar to the general population are restored once remission is induced.

Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle‐aged men compared with those in young men

Abstract: Summary background Conflicting views are reported on the association between advancing age and gradually diminishing concentrations of serum total testosterone in men. The putative loss of diurnal rhythm in serum total testosterone in older men is reported to be in part due to low concentrations in the morning when compared to concentrations found in young men. We have measured total, free and bioavailable testosterone along with SHBG in samples taken every 30 min throughout a 24-h period in 10 young and eight middle-aged men. results Both young and middle-aged men displayed a significant diurnal rhythm in all variables, with a minimum fall of 43% in total testosterone from peak to nadir in all subjects. Subjecting the data to a time series analysis by least squares estimation revealed no significant difference in mesor (P = 0·306), amplitude (P = 0·061) or acrophase (P = 0·972) for total testosterone between the two groups. Comparing bioavailable testosterone in the two groups revealed no significant difference in mesor (P = 0·175) or acrophase (P = 0·978) but a significant difference (P = 0·031) in amplitude. Both groups display a significant circadian rhythm (middle-aged group P < 0·001; young group P = 0·014). Free testosterone revealed a highly significant rhythm in both the young group (P < 0·001) and the middle-aged group (P = 0·002), with no significant difference between the groups in mesor (P = 0·094) or acrophase (P = 0·698). Although analysis of the SHBG data revealed a significant rhythm in the young group (P = 0·003) and the older group (P < 0·001), the acrophase occurred in the mid afternoon in both groups (15·12 h in the young and 15·40 h in the middle-aged). The older men had a significantly greater amplitude (P = 0·044) but again no significant difference was seen in mesor (P = 0·083) or acrophase (P = 0·477) between the two groups. Acrophases for total, bioavailable and free testosterone occurred between 07·00 h and 07·30 h; for SHBG the acrophase occurred at 15·12 h in the young group and 15·40 h in the middle-aged group. conclusions The study suggests that the diurnal rhythm in these indices of androgen status is maintained in fit, healthy men into the 7th decade of life.

Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects

Abstract: objective Sex differences are found in most components of the insulin resistance syndrome and the associated cardiovascular risk profile. These differences are attributed to sex-specific sex steroid profiles, but the effects of sex steroids on the individual components of the insulin resistance syndrome remain incompletely understood. design Prospective, intervention study. subjects In 37 young (age range 16?36 years), nonobese [body mass index (BMI) <29], transsexual subjects, effects of ethinyl oestradiol (100 µg/day) + cyproterone acetate (100 mg/day) administration were evaluated in 20 male-to-female transsexuals and of testosterone-ester administration [250 mg intramuscularly (i.m.)/2 weeks] in 17 female-to-male transsexuals. measurements We studied lipid spectrum, postheparin hepatic lipase (HL) and lipoprotein lipase (LPL) activity, blood pressure, glucose utilization (by euglycaemic hyperinsulinaemic clamp), and fat areas (by magnetic resonance imaging) at baseline and during 1-year cross-sex hormone administration. results Oestrogens + antiandrogens increased high-density lipoprotein (HDL)-cholesterol and decreased LDL-cholesterol, and HL activity, which are considered beneficial. But this combination also increased triglycerides, blood pressure, subcutaneous fat and visceral fat, and decreased the LDL-particle size, LPL activity and insulin sensitivity, which are all considered detrimental. Testosterone reduced HDL-cholesterol and the LDL-particle size, and increased triglycerides and HL activity. An android fat distribution was induced (i.e. decreased subcutaneous and increased visceral fat). Blood pressure, total and LDL-cholesterol, LPL activity and insulin sensitivity were mainly unaffected. conclusions The effects of cross-sex hormone treatment ? in the dosages used in this study ? in healthy, nonobese, young transsexual subjects do not show unequivocally that female sex steroids, given in large amounts to male subjects, have beneficial effects on cardiovascular profile and that high dose testosterone administration to female subjects is detrimental with respect to cardiovascular risk.

Postoperative surveillance of clinically nonfunctioning pituitary macroadenomas: markers of tumour quiescence and regrowth

Abstract: Summary BACKGROUND Postoperative management of clinically nonfunctioning pituitary adenomas (NFPA) presents difficult challenges. There are no good serum markers for presence or growth of the tumour, medical treatment is not effective and radiotherapy carries the risk of significant side-effects. OBJECTIVE The purpose of this study was to investigate the natural history and biological behaviour of surgically treated NFPA, with a special effort to identify characteristics indicative of a more aggressive course that could assist in the clinical decision-making process. STUDY DESIGN Patients operated on at our institution for NFPA undergo uniform routine clinical follow-up at the endocrine clinic. Magnetic resonance imaging (MRI) studies are performed 3, 6 and 12 months after transsphenoidal surgery and yearly thereafter for the first 5 years. Subsequently, imaging is performed once every 2 years or as clinically indicated. From 1992 onwards, no patient received immediate postoperative radiation therapy. PATIENTS One hundred and twenty-two patients (78M/ 45F) operated on at our institution since 1989 and with a minimal follow-up of 1 year comprised the study group. MEASUREMENTS Tumour size and characteristics were determined by MRI using a modification of Hardy’s and Wilson’s classifications. Maximal tumour height was also recorded and the information was routinely stored in a computerized database. RESULTS Mean (± SD) follow-up was 51 ± ± ± 31 months. Fourteen patients received postoperative radiation therapy. Subsequent tumour growth was observed in five of them, reduction in tumour size in four and no size changes in five. One hundred and eight patients did not receive postoperative radiation. Tumour enlargement occurred in 41 of 78 and in six of 30 patients with and without residual tumour after operation ( P = 0·0024). The presence of cavernous sinus invasion before surgery [ P = 0·02, odds ratio (OR) 2·72; confidence interval (CI) 1·1‐6·43] and the extent of suprasellar extension in the postoperative tumour remnant ( P = 0·0054 for presence of stage A, OR 4·4; 95% CI 1·5‐12·5; and P = 0·012 for presence of stages B or C, OR 16·2; CI 1·8‐144) were strong independent predictors of tumour enlargement. CONCLUSION Our data may ease the selection of patients in whom radiation therapy is likely to be necessary for tumour control, and confirms that close postoperative follow-up is an adequate primary approach in low-risk patients.

Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency

Abstract: Summary background and aims Autoimmune thyroiditis is one of the most common autoimmune disorders. Autoantibodies against the thyroid gland, with thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (Tg-Ab) as the most common autoantibodies, can often be demonstrated in serum in population surveys. In the present study we evaluated if TPO-Ab and Tg-Ab tend to develop in parallel or whether one or the other may be more prevalent in subsets of the population. methods In a cross-sectional comparative study, performed in two areas of Denmark with mild and moderate iodine deficiency, 4649 randomly selected subjects in age groups between 18 and 65 years were examined. Blood tests were analysed for TPO-Ab and Tg-Ab using assays based on the radioimmunoassay (RIA) technique. The participants answered questionnaires, were clinically examined and had urine samples collected. results The overall prevalence rate of thyroid autoantibodies (TPO-Ab and/or Tg-Ab) was 18·8%. The prevalence rates of TPO-Ab and Tg-Ab were similar (13·1 vs. 13·0%). Both antibodies were more frequent in females than in males, and in females the prevalence rates increased with age. In the age group 60–65 years thyroid antibodies were more frequently measured in sera from moderate than from mild iodine-deficient area (P = 0·02), whereas no differences were seen in younger subjects. In 38·8% of participants with thyroid autoantibodies in serum, both antibodies were present. In sera with both TPO-Ab and Tg-Ab present the concentrations of the antibodies were generally higher than in sera with only one type of antibody present. conclusion The prevalence rates of TPO-Ab and Tg-Ab were similar in this large population survey. The results suggest that TPO-Ab and Tg-Ab predominantly develop due to a general alteration in the immune system, whereas specific antigenic mechanisms are probably of less importance. However, further studies are needed to clarify the mechanisms involved in the development of thyroid autoantibodies.

TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves' ophthalmopathy patients.

Abstract: Objective From in vitro studies using cultures of orbital fibroblasts, it has become clear that cytokines play an important role in the orbital inflammation in Graves' ophthalmopathy (GO). Orbital fibroblasts seem to be the key target cells of the autoimmune attack, and they are able to express the TSH receptor (TSH-R). In vivo data on the presence of cytokines in orbital tissues are sparse, and mostly limited to samples obtained from patients with endstage, inactive GO; the same holds true for the presence of the TSH-R. The aim of the present study was to determine whether the cytokine profile and TSH-R expression differ in the active vs. the inactive stage of GO. Design and measurements Orbital fat/connective tissue was obtained from six patients with active, untreated GO undergoing emergency orbital decompression, and from 11 patients with inactive GO subjected to rehabilitative decompressive surgery. The mRNA levels of various cytokines and the TSH-R were assessed by real-time polymerase chain reaction (PCR) using the LightCycler. Data are expressed as ratios (unknown mRNA/beta-actin mRNA). Results Active GO patients had much higher TSH-R expression than inactive patients: 4/0-24 (median value/range) vs. 0/0-9, P = 0.01. TSH-R expression was related to the Clinical Activity Score (r = 0.595, P = 0.015). Patients with active GO compared to those with inactive GO had higher mRNA levels of the proinflammatory cytokines interleukin-1beta (IL-1beta) (445/153-877 vs. 0/0-455, P = 0.001), IL-6 (1583/968-18825 vs. 559/0-7181, P = 0.01), IL-8 (1422/38-7579 vs. 32/0-1081, P = 0.046) and IL-10 (145/58-318 vs. 27/0-189, P = 0.002). In active GO there also existed a trend towards a predominance of T helper 1 (Th1)-derived cytokines as evident from higher IL-2 (37/0-158 vs. 0/0-68, P = 0.043), interferon-gamma (IFN-gamma) (20/0-79 vs. 0/0-16, P = 0.12) and IL-12 (2.3/0-14.8 vs. 0/0-1.6, P = 0.10) mRNAs. IL-1 receptor agonist (IL-1RA), IL-2 receptor (IL-2R), IL-3, IL-4, IL-5, IL-13, IL-18 and tumour necrosis factor-alpha (TNF-alpha) mRNAs were similar in both groups. Conclusions These data show that at the mRNA level, TSH-R expression is largely present only during the active stages of GO. The active phase is characterized by the presence of proinflammatory and Th1-derived cytokines, whereas other cytokines, among them Th2-derived cytokines, do not seem to be linked to a specific stage of GO.

Musculoskeletal manifestations in patients with thyroid disease

Abstract: Summary objective Thyroid dysfunction may cause musculoskeletal symptoms. We have evaluated the prevalence of adhesive capsulitis, Dupuytren's contracture, trigger finger, limited joint mobility and carpal tunnel syndrome in a series of patients with various thyroid diseases and differing levels of function. design and patients Patients with euthyroid (diffuse and/or nodular) goitre, Hashimoto's thyroiditis, Graves’ disease, toxic nodular goitre, toxic diffuse goitre and patients with goitre who had partial thyroidectomy were included in the study (n = 137). Neurological and musculoskeletal examinations were performed after a standardized symptom questionnaire. The prevalence of musculoskeletal problems was analysed with respect to thyroid function and thyroid autoantibody status. measurements Serum concentrations of free T3, free T4, TSH and thyroglobulin and thyroperoxidase antibodies were determined. Serum levels of creatine kinase, lactate dehydrogenase, calcium and phosphate along with erythrocyte sedimentation rate were measured to exclude other causes of musculoskeletal complaints. results When the study group (n = 137) was divided according to thyroid status, 30·6% (n = 42) were thyrotoxic, 16·8% (n = 23) had subclinical thyrotoxicosis, 28·5% (n = 39) were euthyroid, 7·3% (n = 10) had subclinical hypothyroidism and 16·8% (n = 23) were hypothyroid. Overall, adhesive capsulitis was found in 10·9% (n = 15), Dupuytren's contracture in 8·8% (n = 12), limited joint mobility in 4·4% (n = 6), trigger finger in 2·9% (n = 4) and carpal tunnel syndrome in 9·5% (n = 13) of the patients. The prevalence of adhesive capsulitis was highest in patients with subclinical thyrotoxicosis (17·4%); Dupuytren's contracture, limited joint mobility and carpal tunnel syndrome were commonest in hypothyroid patients (21·7%, 8·7% and 30·4%, respectively). Trigger finger occurred in 10% of patients with subclinical hypothyroidism. When these prevalences were analysed with respect to thyroid status, carpal tunnel syndrome was significantly more prevalent in the hypothyroid group (P = 0·004). When thyroperoxidase antibody-positive and -negative patients were compared, adhesive capsulitis negatively (P = 0·03, r =−0·18) and trigger finger positively correlated with (P = 0·03, r = 0·21) thyroperoxidase antibody existence. conclusions These results demonstrate that musculoskeletal disorders often accompany thyroid dysfunction. In addition to the well-known observation that these disorders are common in patients with hypothyroidism, they are also observed in patients with thyrotoxicosis. Patients with thyroid dysfunction should be questioned for musculoskeletal complaints and referred to a specialist if necessary.

SPECT/CT hybrid imaging with 111In-pentetreotide in assessment of neuroendocrine tumours

Abstract: Summary objective Somatostatin receptor scintigraphy (SRS) of neuroendocrine (NE) tumours is often challenging because of minute lesion size and poor anatomic delineation. This study evaluates the impact of sequentially performed single-photon emission computed tomography (SPECT)/CT fusion on SRS study interpretation and clinical management of these tumours. patients and design Seventy-two patients were studied with routine SRS and SPECT/CT at 4, 24 and optionally 48 h after injection of 222 MBq 111In-pentetreotide. Forty-five patients were evaluated for carcinoid, 15 for islet cell tumour, seven for metastatic NE tumour, four for medullary thyroid carcinoma, and one patient had ophthalmopathy. SPECT/CT induced improvement in the interpretation of SPECT and conventional CT and resultant clinical management changes were recorded. results SRS was negative in 28 patients and positive in 44 patients. SPECT/CT provided no additional information in 48 patients, including all 28 negative studies. SPECT/CT improved localization of the SPECT-detected lesions in 23 of the 44 positive studies. It defined the extent of disease in 17, showed unsuspected bone involvement in three, and differentiated physiological from tumour uptake in three studies. SPECT/CT affected the clinical management in 10 patients, altered the surgical approach in six, spared unnecessary surgery in two, and modified the therapeutic modality in two patients. conclusions SPECT/CT affected the diagnostic interpretation of SRS in 32% of the patients and induced changes in management in 14% of the patients.

The effect of body weight and weight loss on thyroid volume and function in obese women.

Abstract: Summary objective Thyroid volume and thyroid function may vary in obese and nonobese women. It is not known whether weight loss could affect thyroid volume and function in obese subjects. patients and methods The study population consisted of 98 premenopausal euthyroid obese [body mass index (BMI) = 30 kg/m2] women (mean age 40·5 ± 11·4 years) and 31 nonobese (BMI < 25 kg/m2) women (mean age 38·6 ± 12·9 years). Weight, height, BMI, waist circumference, body fat percentage and fat weight of all subjects were measured. Thyroid function and thyroid ultrasonography were performed at baseline and after 6 months of obesity treatment. Subgroup analysis was done according to weight loss. results Thyroid volume (P = 0·021) and TSH concentration (P = 0·047) were higher; free T3 (P 10% body weight. There was a positive correlation between the changes of thyroid volume and the change of body weight (r = 0·341, P = 0·009) and the change of body fat weight (r = 0·406, P = 0·013). conclusions Our study suggests that thyroid volume and function may vary in obese women in association with body weight and fat mass; > 10% weight loss may affect thyroid volume and function, which however, is clinically insignificant.

Ghrelin concentrations in healthy children and adolescents.

Abstract: Summary objective In addition to its regulation by GH releasing hormone (GHRH) and somatostatin, release of GH from the pituitary is modulated by a third factor, ghrelin, which is expressed in high concentration in the stomach and is present in the circulation. Ghrelin has also been shown to cause weight gain by increasing food intake and decreasing fat utilization. Ghrelin is a potential candidate hormone to influence nutrient intake and growth. Its role through normal childhood and adolescence has not been fully defined. design Cross-sectional study in 121 healthy children (65 male, 56 female) aged 5–18 years, in whom height, weight, body mass index (BMI), pubertal status and measurements of IGF-I, IGFBP-3, IGFBP-1 and leptin were available. methods Serum ghrelin concentrations have been measured in radioimmunoassay (RIA; Phoenix, AZ, USA) that detects active and inactive human ghrelin. Relationships between ghrelin and anthropometric data and growth factors were assessed by correlation and regression analyses. results Ghrelin was detected in all samples, with a median concentration of 162 pg/ml, range 60–493 pg/ml. Prepubertal children had higher ghrelin concentrations than those in puberty [218 pg/ml (n = 42) and 157 pg/ml (n = 79), P < 0·001], with significant negative correlations between ghrelin and age (rs = −0·39, P < 0·001) and pubertal stage (rs = −0·42, P < 0·001). The decrease in ghrelin with advancing pubertal stage/age was more marked in boys than girls. In the whole group, ghrelin was negatively correlated to BMI SD (rs = −0·24, P = 0·006) and to weight SD (rs = −0·24, P = 0·008) but not height sds. Ghrelin was also negatively correlated to IGF-I (rs = −0·48, P < 0·001), IGFBP-3 (rs = −0·32, P < 0·001) and leptin (rs = −0·22, P = 0·02) but not IGF-II. It was positively related to IGFBP-1 (rs = +0·46, P < 0·001). In stepwise multiple regression, 30% of the variability in ghrelin through childhood could be accounted for by log IGF-I (24%) and log IGFBP-1 (6%). conclusions The fall in ghrelin over childhood and with puberty does not suggest that it is a direct growth-promoting hormone. However in view of the negative relationship with IGF-I and the positive relationship with IGFBP-1, this fall in ghrelin could facilitate growth acceleration over puberty.

Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas: relationships to clinical tumour behaviour

Abstract: Summary objective Pituitary tumour transforming gene (PTTG) encodes a multifunctional protein that is implicated in initiating and perpetuating pituitary adenoma growth. PTTG appears to have key regulatory functions in determining control of many fundamental cellular events including mitosis, cell transformation, DNA repair and gene regulation. Several of these events are mediated through interactions with PTTG binding factor (PBF) and fibroblast growth factor-2 (FGF-2). Given this background, we have determined the expression of PTTG, PBF, FGF-2 and its receptor FGF-R-1 in a large cohort of pituitary adenomas and have sought associations between levels of gene expression and clinical markers of tumour behaviour. patients and methods We used real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analyses to measure PTTG, PBF, FGF-2 and FGF-R-1 expression in ex vivo pituitary tumours (N = 121). Clinical data, including accurate radiological assessment of tumour characteristics, were used to determine any associations between gene expression and tumour behaviour. results PTTG was increased significantly (fivefold, P = 0·005) in adenomas compared with normal pituitaries. We also demonstrated that PBF was similarly raised in adenomas (sixfold, P = 0·0001), and was significantly correlated with PTTG expression. FGF-2 and its receptor FGF-R-1 were also raised in adenomas compared with normal pituitary tissue. Moreover, significantly enhanced expression of FGF-R-1 was observed in invasive adenomas compared with other pituitary tumours. conclusions Our data support a fundamental role for PTTG-mediated upregulation of FGF-2 signalling in pituitary tumorigenesis and growth, and suggest that receptor-mediated mechanisms of growth factor action may be critically important. Further prospective studies are required to determine whether measurement of FGF-R-1 mRNA will be of clinical use as a prognostic marker in patients with pituitary adenomas.

Risk factors for and prevalence of thyroid disorders in a cross‐sectional study among healthy female relatives of patients with autoimmune thyroid disease

Abstract: Summary objective Autoimmune thyroid disease (AITD) is a common disorder especially in women, and both genetic and environmental factors are involved in its pathogenesis. We wanted to gain more insight into the contribution of various environmental factors. Therefore, we started a large prospective cohort study in subjects at risk of developing AITD, for example healthy female relatives of AITD patients. Here we report on their baseline characteristics. subjects Only first- or second-degree female relatives of patients with documented AITD were included. measurements Smoking habits, oestrogen use, pregnancy history and iodine exposure were assessed by questionnaires, and correlated to the thyroid function and antibody status. results Of 803 subjects, 440 came from families with more than one patient with documented AITD. Of these families, 33% had documented cases of both Graves’ disease and Hashimoto's thyroiditis. Although the subjects were in self-proclaimed good health, 3·6% were found to have hypothyroidism (overt disease in 1·3%) and 1·9% had hyperthyroidism (overt disease in 0·4%). These patients were older than the euthyroid subjects and were mostly positive for thyroid peroxidase (TPO) antibodies. Oestrogen use was associated with a lower rate of hyperthyroidism [relative risk (RR) 0·169; 95% confidence interval (CI) 0·06–0·52], whereas having been pregnant was associated with a higher relative risk for hyperthyroidism (RR 6·88; 95% CI 1·50–30·96). Of the 759 euthyroid subjects, 24% had TPO antibodies. Smoking and oestrogen use were negatively correlated with the presence of TPO antibodies. In the euthyroid subjects, TPO antibody titre correlated positively with TSH levels (r = 0·386; P < 0·001). conclusions The high prevalence of evidence for autoimmune thyroiditis at baseline supports the importance of genetic factors in its pathogenesis. The co-occurrence of Hashimoto's thyroiditis and Graves’ disease within one family suggests a common genetic basis for these diseases. Oestrogen use is associated with a lower risk, and pregnancy with a higher risk for developing hyperthyroidism. The positive correlation between TPO antibody titres and TSH levels in euthyroid subjects suggests that TPO antibodies are indeed a marker of future thyroid failure.

The relation between two polymorphisms in the glucocorticoid receptor gene and body mass index, blood pressure and cholesterol in obese patients.

Abstract: Summary OBJECTIVE We have recently reported that, in healthy elderly Dutch individuals, a N363S polymorphism in the glucocorticoid receptor (GR) gene is associated with higher sensitivity to low-dose dexamethasone (0·25 mg), evaluated as both cortisol suppression and insulin response, and with an increased body mass index (BMI). In the present study we investigated the role of the N363S polymorphism, and a Bcl I restriction site polymorphism in a group of Italian patients with severe obesity. DESIGN Two hundred and seventy-nine patients (mean BMI 45·9 ± 0·9 kg/m 2 ) were genotyped using both PCR-restriction fragment length polymorphism analysis and Taqman Sequence Detection System. Determination of several metabolic and antropometric parameters was also performed in order to correlate them to the genotype. RESULTS In this group of obese patients, 13 subjects (eight female, five males) were heterozygous for the N363S variant (allelic frequency 2·3%) and had significantly higher BMI ( P < 0·04), resting energy expenditure ( P < 0·03) and food intake ( P < 0·01) when compared to wild-type homozygotes. When the data were analysed according to sex, female heterozygotes for the N363S allele had significantly higher BMI ( P = 0·04), resting energy expenditure ( P = 0·03) and food intake ( P = 0·008) than obese women with the wild-type 363 GR gene. Male carriers of this variant also had higher values for these variables although the differences did not reach statistical significance. A case‐control study with homozygous wild-type obese subjects which were age-, sex- and BMI-matched, revealed no difference in resting energy expenditure and food intake. The allele frequency of the Bcl I variant was 27% (89 females and 41 males out of 269 subjects). No differences in anthropometric and metabolic parameters were found between subjects heterozygous or homozygous for this variant GR in this obese population. However, when we studied the effect of the presence of the Bcl I polymorphism and the N363S variant in the same individual, we found that the subjects who carried both polymorphisms had a tendency towards higher systolic and diastolic blood pressure and significantly higher total and LDLcholesterol levels ( P = 0·005 and P = 0·05, respectively). DISCUSSION Taking the results of this study and those obtained in the Dutch population, we speculate that heterozygous carriers of the N363S variant who develop obesity, may become even more obese, possibly because they have a hypersensitive insulin response and thus, via activation of lipogenesis, store fat more efficiently. Furthermore, these data suggest that N363S carriers who carry the Bcl I polymorphism as well, tend to have a slightly unfavourable cardiovascular profile.

Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche.

Abstract: Summary objective Precocious pubarche (PP) in girls is associated with hyperinsulinaemia and dyslipidaemia of prepubertal onset, and with ovarian hyperandrogenism and ovulatory dysfunction in adolescence, particularly if they also had prenatal growth restraint and postnatal growth acceleration. Hyperinsulinaemia may be the pathogenic key factor, possibly amplified by hyperandrogenaemia. While such PP girls do not have increased body mass index (BMI), we hypothesized that body fat mass and fat distribution may differ between PP girls and matched controls, and may relate to insulin and androgen levels. patients and design Sixty-seven PP girls (age range 6·0–18·0 years) and 65 control girls matched for age and pubertal stage (5·9–18·0 years) had height, weight, waist and hip circumferences measured, and dual-energy X-ray absorptiometry (DXA) assessment of total body fat mass, and fat mass in abdominal and truncal regions. All girls had fasting plasma glucose, serum insulin, lipids, testosterone and SHBG levels measured; PP girls also had a standard 2-h oral glucose tolerance test (oGTT). results Despite no differences in BMI, PP girls had significantly larger waist circumference, waist-to-hip ratio, total fat mass, percentage fat mass, abdominal fat mass, and truncal fat mass vs. controls in each pubertal stage. Overall, fasting insulin levels, free androgen index (FAI) and blood lipid levels were more closely related to central fat than to total body fat mass. In a multiple regression analysis, truncal fat mass was independently related to both fasting insulin (P = 0·009) and FAI (P < 0·0001). Abdominal fat mass was inversely related to birthweight (r = −0·25, P = 0·001). In PP girls, central fat mass was positively related to insulin levels after oGTT (truncal fat vs. 30 min insulin; r = 0·46, P < 0·0005). conclusions Precocious pubarche girls had excess total body and central fat mass throughout all pubertal stages, and increased central fat was related to hyperinsulinaemia and hyperandrogenaemia. It remains to be verified whether body composition in PP girls can be normalized by insulin-sensitization and/or antiandrogen therapy.

Effects of low‐iodide diet on postsurgical radioiodide ablation therapy in patients with differentiated thyroid carcinoma

Abstract: OBJECTIVE Most patients with differentiated thyroid carcinoma (DTC) undergo total thyroidectomy followed by routine radioiodide thyroid remnant ablation. Most centres that routinely perform radioiodide ablation prescribe a low-iodide diet (LID) to increase the radioiodide accumulation in thyroid remnants. The efficacy of an LID on thyroid remnant ablation, however, has never been demonstrated convincingly. DESIGN AND METHODS In a retrospective study, we studied two groups of DTC patients without distant metastases, who had received either a standard diet or an LID during ablation (LID group, n = 59, and control group, n = 61). Both groups were compared for radioiodide uptake in thyroid remnants during ablation and efficacy parameters of remnant ablation, 6 months after ablation. A subgroup without extrathyroidal tumour growth was analysed separately (stages T1-3, NO). RESULTS In the total group, the LID during ablation decreased the 24-h urinary iodide excretion to 26.6 μg compared with 158.8 μg in controls whereas radioiodide uptake in thyroid remnants was increased by 65% (P < 0.001). Six months after ablation, patients were investigated after thyroid hormone withdrawal. In the total group, no significant effects of the LID during ablation were observed on thyroglobulin (Tg) or the percentage of patients with persistent neck activity after 185 MBq 131 I. However, in the LID group, 65% of patients without Tg antibodies had undergone successful ablation (defined by absent neck activity and Tg<2 μg/l) compared with 48% in the control group (P < 0.001). In the subgroup (T1-3, NO), 8% of the patients who had undergone the LID had Tg ≥ 2 μg/l vs. 32% in the control group (P= 0.012), whereas successful ablation was achieved in 71% of patients without Tg antibodies in the LID vs. 45% in the control group (P< 0.001). CONCLUSION We conclude from this study that a low-iodide diet during thyroid remnant ablation improves the efficacy of this treatment.

Hyperadiponectinaemia in anorexia nervosa

Abstract: OBJECTIVE: Adiponectin (ApN) is a fat-derived hormone that enhances insulin sensitivity, controls body weight, prevents atherosclerosis and negatively regulates haematopoiesis and immune functions. In contrast to many proteins secreted by adipose tissue, the circulating level of ApN falls in obesity and insulin resistance states. The influence of starvation-induced depletion of fat stores on ApN concentrations is yet unknown. We therefore investigated plasma ApN in anorexia nervosa (AN). PATIENTS AND DESIGN: We measured plasma ApN in 26 female anorectic patients and examined its relationships to several anthropometric or metabolic parameters. Twenty-four age-matched healthy female controls (C) were also studied. RESULTS: Body mass index (BMI) and fat mass were markedly decreased in AN. However, plasma ApN levels were 30% higher in anorectic than in control subjects (P < 0.01), while a reverse pattern was observed for leptin concentrations. When normalized for fatness, ApN values almost doubled in AN. ApN levels were negatively correlated with BMI and fat mass (P < 0.05 in the combined population, AN + C). Insulin sensitivity tended to be 40% higher in AN (n = 7) than in C (n = 12) subjects, and plasma ApN levels were positively correlated with insulin sensitivity (P < 0.05 in AN + C subgroups). Total and low density lipoprotein (LDL)-cholesterol were higher, or tended to be higher, in AN, but there were no correlations between plasma ApN and plasma lipids. By contrast, ApN was related to the lipid profile, in a manner consistent with its antiatherogenic role, in healthy controls [i.e. negatively correlated with triglycerides, total and LDL-cholesterol and total/high density lipoprotein (HDL) cholesterol; P < 0.05 or less for each parameter]. In a multiple regression analysis, BMI and insulin sensitivity in AN were independent determinants for ApN levels, explaining up to approximately 80% of the variance in this measure. CONCLUSIONS: Plasma adiponectin levels are increased in anorexia nervosa. This may, at least in part, be due to the lack of negative feedback exerted by fat mass on adiponectin production and/or to enhanced insulin sensitivity. We speculate that hyperadiponectinaemia could, in turn, contribute to maintain a state of enhanced insulin sensitivity and possibly exacerbate haematological and infectious complications of anorexia nervosa.

Serum concentrations of adipocytokines in patients with hyperthyroidism and hypothyroidism before and after control of thyroid function.

Abstract: OBJECTIVE Adipose tissue is a hormonally active system that produces and releases different bioactive substances. Leptin, adiponectin and resistin are some of the recently discovered adipocytokines that participate in the regulation of intermediate metabolism. The aim of this study was to evaluate the circulating levels of leptin, adiponectin and resistin in patients with thyroid dysfunction before and after normalization of thyroid function with appropriate therapy. PATIENTS AND MEASUREMENTS We studied 20 patients with hyperthyroidism (16 women and 4 men; mean age 47.2 +/- 3.9 years) and 20 patients with hypothyroidism (17 women and 3 men; 51.5 +/- 4.1 years). A group of 20 euthyroid subjects served as control group. Patients were evaluated at the time of diagnosis and again after normalization of thyroid function with appropriate therapy. Serum concentrations of free T4 (FT4), total T3, TSH, insulin, leptin, adiponectin and resistin were measured in all subjects. RESULTS Hyperthyroid patients showed significantly decreased leptin levels in comparison with controls (11.0 +/- 1.1 vs. 30.4 +/- 5.0 microg/l, P < 0.001). No significant differences in adiponectin levels between hyperthyroid and control groups were found (27.8 +/- 4.0 vs. 46.0 +/- 12.0 mg/l, NS). Patients with hyperthyroidism exhibited reduced resistin levels in comparison with euthyroid subjects (6.4 +/- 0.8 vs. 8.4 +/- 0.7 microg/l, P < 0.05). Normalization of circulating thyroid hormone was accompanied by a nonsignificant increase in leptin levels (12.9 +/- 1.7 microg/l, P < 0.01 vs. control) and no significant modification both in adiponectin (32.0 +/- 7.1 mg/l, NS) and resistin (5.4 +/- 0.7 microg/l, NS) levels. Adjustment of adipocytokine concentrations for body mass index (BMI) showed that treatment of hyperthyroidism induced a significant reduction in adjusted resistin concentrations (0.21 +/- 0.03 vs. 0.28 +/- 0.03 microg/l/BMI units, P < 0.05), with no changes in adjusted leptin and adiponectin. Hypothyroid patients showed significantly lower leptin levels compared with the controls (16.0 +/- 3.5 vs. 30.4 +/- 5.0 microg/l, P < 0.05). Adiponectin levels in patients with hypothyroidism (71.8 +/- 16.0 mg/l) were similar to those in the control group and were not modified with therapy. Resistin levels were significantly reduced among hypothyroid patients (5.8 +/- 1.0 microg/l, P < 0.05), and were not increased after levothyroxine therapy. A significant rise in BMI-corrected leptin levels was observed after replacement therapy, with no changes in adiponectin- and resistin-corrected values. CONCLUSIONS The results suggest that (1) low serum leptin levels are present in both hyperthyroid and hypothyroid patients but are only increased after therapy in the latter; (2) resistin might be implicated in the insulin resistance state that accompanies thyrotoxicosis; and (3) inadequate secretion of adiponectin seems to have no role in metabolic changes associated with thyroid dysfunction.

Non-functioning pituitary adenomas with positive immunoreactivity for ACTH behave more aggressively than ACTH immunonegative tumours but do not recur more frequently.

Abstract: Summary objectives Anecdotal reports have suggested that silent corticotroph tumours behave in an aggressive fashion; however, clear comparative data with other non-functioning adenomas (NFAs) are lacking. The aims of the study were, first, to review the natural history of those non-functioning pituitary adenomas with positive immunoreactivity for ACTH and secondly, to determine whether this subgroup behave more aggressively than ACTH immunonegative NFAs by means of comparison with existing departmental data. methods and patients Twenty-eight patients (16 men, mean age 51·3 years) who underwent transsphenoidal surgery in Oxford between 1975 and 2001 for clinically non-functioning adenomas where the subsequent immunostaining was positive for ACTH were identified from the patient database. All patients with silent corticotroph tumours who presented during this time period have been included in the analysis; three of the patients have subsequently died but none have been lost to follow-up. The mean follow-up period was 7·4 years (range 0·5–26·9 years) and the results were compared with departmental data for NFAs which were immunonegative for ACTH. None of the patients had clinical evidence of Cushing's syndrome. Tumour invasiveness was classified according to the modified Hardy criteria (Grade 1 = microadenoma ( 1 cm) ± suprasellar extension, Grade 3 = local invasion with bony destruction and tumour in sphenoid/cavernous sinus and Grade 4 = central nervous sytem (CNS) spread or extracranial spread, i.e. metastatic). Tumour recurrence was defined as an increase in tumour size compared with the first postoperative scan which was used as a baseline. Visual field defects were documented in 79% of the 28 patients at presentation compared to 69% in the non-functioning population as a whole (P = 0·3). The preoperative imaging in the silent corticotroph group (13 CT, 14 MRI and one air encephalogram) revealed 68% Grade 2 and 32% Grade 3 adenomas. results The recurrence rate in the ACTH immunopositive tumours was 32% at a mean of 5·8 years (range 1–16 years) which was not significantly different from the 33% recurrence rate previously recorded in the ACTH immunonegative tumours (P = 0·9). Two of the patients with silent corticotroph adenomas have suffered multiple recurrences; one patient has had three operations and two courses of radiotherapy for two episodes of recurrence and one patient has had four operations, two courses of radiotherapy and gamma knife therapy after three recurrences in total. In contrast, no patient with an ACTH immunonegative tumour has required more than one course of treatment for tumour regrowth. conclusions This is the first single-centre comparative study of a series of clinically silent ACTH immunopositive tumours and has demonstrated that although they do not recur more often than ACTH immunonegative tumours, when they do regrow they show a more aggressive course. The practical implication of this is that there is no evidence for different postoperative imaging and radiotherapy protocols for ACTH immunopositive and immunonegative NFAs at initial presentation. However, if regrowth of a silent corticotroph tumour does occur then very careful monitoring is essential, after further treatment.

Giant prolactinomas in men: efficacy of cabergoline treatment

Abstract: Summary objective The term ‘giant prolactinoma’ can be used for tumours larger than 4 cm in diameter and/or with massive extrasellar extension. Cabergoline (CAB), a long-lasting dopamine agonist (DA), safe and well tolerated, is effective in normalizing PRL levels and inducing tumour shrinkage in micro- and macroprolactinomas. The purpose of this prospective study was to evaluate the efficacy and safety of CAB also for giant prolactinomas. patients and methods Ten men with giant prolactinomas with a median age of 44·8 years were treated with CAB. Before CAB, four patients had previously undergone transsphenoidal surgery without modifying the parasellar extension of the tumour or their visual defects. Pretreatment serum prolactin (PRL) levels ranged between 1230 and 22 916 µg/l (mean ± SEM: 5794 ± 1996) and tumour volume was between 21·8 and 105·5 cm3 (mean ± SEM: 50·7 ± 8·8). CAB was administered at an initial low dose of 0·5 mg three times a week and, in five patients who did not achieve serum PRL normalization, the dose was progressively increased up to 10·5 mg/week. The duration of treatment was 13–68 months (mean 38·9). PRL levels and pituitary target organ hormones were assayed before, after 30 days and then every 3 months after the beginning of CAB treatment. Magnetic resonance imaging (MRI) was carried out before, after 1–3 months, after 6 months and then every 10–12 months to evaluate tumour shrinkage. results In every patient, a significant PRL decrease (P = 0·0086) of at least 96% of the pretreatment values occurred (from 5794 ± 1996 to 77 ± 38, mean ± SEM); a persistent normalization of PRL levels was achieved in five out of 10 patients (50%) beginning from the first 3–6 months of CAB treatment (only one patient needed 12 months of therapy). A significant tumour shrinkage (P = 0·0003) was achieved after 12 months of therapy in nine out of 10 patients (90%), with a volume reduction greater than 95% in three, of 50% in four and 25% in two patients. Tumour volume decreased from 50·7 ± 8·8 to 28·6 ± 9·4 and then to 22·3 ± 8·8 cm3 (mean ± SEM) after 6 and 12 months of CAB treatment, respectively. An improvement of visual field defects (VFD) was obtained in six of the seven patients presenting visual impairment before CAB treatment. Among the eight patients presenting libido and potency (L-P) failure, five normalized their PRL levels. In two of these a complete restoration of libido and potency was observed. Three patients with secondary hypoadrenalism and a patient with secondary hypothyroidism were treated with substitutive therapy during all the study time. The drug was well tolerated by all patients and no one discontinued the therapy. conclusions These data suggest that, in giant, aggressive prolactinomas, CAB represents a first-line therapy effective in reducing PRL levels and determining tumour shrinkage.

The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing's syndrome

Abstract: Summary objective It has been reported previously that the paired interpretation of the corticotrophin-releasing hormone (CRH) test and the 8-mg dexamethasone suppression test (HDDST) could have higher diagnostic power than any single test in the differential diagnosis of ACTH-dependent Cushing's syndrome. This finding has not been confirmed thereafter in large series. The aim of the present study has been to assess the operating characteristics of either the CRH test or the overnight HDDST and also to evaluate the potential utility of combining the interpretation of both tests in the differential diagnosis of ACTH-dependent Cushing's syndrome. design and patients We have reviewed the medical records of 59 consecutive cases with ACTH-dependent Cushing's syndrome: 49 patients with proven Cushing's disease (CD) and 10 patients with proven ectopic ACTH syndrome (EAS). Univariate curves of the receiver operating characteristics (ROC) have been performed to define the best cut-off values, the sensitivity and the specificity for CRH and overnight HDDST. A comparison between the areas under the ROC curves has also been performed. results For the CRH test, the point on the ROC curve closest to 1 corresponded to a value of ACTH percentage increment of 50%[sensitivity 86% (72·6–94·8) and specificity 90% (55·5–98·3)]. The best threshold for cortisol percentage (30%) increment gave inferior results [sensitivity 61% (45·5–75·6) and specificity 70% (34·8–93·0)]. For the HDDST, the point on the ROC curve closest to 1 corresponded to a value of cortisol decrease from the baseline of 50%[sensitivity 77% (62·7–88·5), specificity 60% (26·4–87·6)]. The area under the ROC curve of the ACTH percentage increment after CRH was significantly greater than the area under the diagonal [0·9 (0·7–1·0), P= 0·0001]. Conversely, the area under the cortisol percentage decrement after dexamethasone was not different from that obtained by chance [0·7 (0·5–0·9), P= ns]. The area under the ROC curve of CRH is significantly greater than that of overnight HDDST (P = 0·03). A correct diagnosis has been achieved by the CRH test in 86·5% of cases and by the HDDST in 73% (P = 0·06). The combination of both tests has given a correct diagnosis in a significantly lower percentage of cases than the CRH test alone (69%, P= 0·04). The bilateral inferior petrosal sinus sampling (BIPSS) has been performed in 29 patients (24 CD, five EAS) who had negative imaging and/or discordant results of the noninvasive tests. Considering the criterion of a central to peripheral ACTH ratio > 3 after CRH stimulation, a correct diagnosis was achieved in all cases. conclusions The present data suggest that the CRH is likely to be the most reliable noninvasive diagnostic procedure for the differential diagnosis of the ACTH-dependent Cushing's syndrome. The criterion for a diagnosis of EAS is an ACTH percentage increment lower than 50%. The use of a combination of tests is not recommended because it does not add valuable information and may even impair the outcome of the CRH test. Cases with discordant results in pituitary imaging and CRH test should undergo BIPSS. The validity of this approach, which is straightforward and easily applicable in clinical practice, should be verified in larger series.

Increased fracture rates in Turner's syndrome: a nationwide questionnaire survey.

Abstract: Summary background and objectives Reduced bone mineral content (BMC) and bone mineral density (BMD) have previously been reported in Turner's syndrome, although appropriate GH treatment and early induction of puberty seem to permit normal bone mass accumulation. Furthermore, an increased risk of fractures and osteoporosis have been reported in a registry study. The aim of the present study was to further characterize the risk of fractures in TS and to explore risk factors, in a historical follow-up survey based on a self-administered questionnaire. study groups The questionnaire was issued to all females with TS (n = 632) in Denmark and to 1888 randomly selected controls (C) matched for age and geographical region. A total of 322 patients (51%) and 1169 controls (62%) returned the questionnaire. results TS women were younger than C (30 years, range: 1–73 years vs. 34 years, range 2–82 years, P < 0·0005), smoked less often (17%vs. 27%, P < 0·0005), and had less frequent spontaneous menstruation (18%vs. 86%, P < 0·0005). In contrast, they used hormonal replacement therapy (HRT) more often (71%vs. 7%, P < 0·0005). The median age at start of HRT was 16 years (range 8–59 years) in TS vs. 42 years (range 12–53 years) in C (P < 0·0005). Above the age of 15 years, 83% of TS and 8% of C used HRT. GH had been used by 37% of TS but only 0·2% of C. Both type 1 and 2 diabetes were increased sevenfold among TS. Altogether, 77 individuals with TS had 109 fractures. The fracture risk was increased in TS [hazard ratio (HR, status) 1·35, confidence interval (CI) 1·04–1·75, P = 0·025]. Time to first fracture was reduced in TS (53 ± 2 vs. 63 ± 1; log-rank P = 0·03). Spontaneous menstruation was protective in females above 13 years of age (HR: 0·70, CI 0·54–0·93, P = 0·012). A history of parental fractures increased the risk (HR 1·92, CI 1·62–2·27, P < 0·001). Fractures of the forearm was more frequent among TS (P = 0·02). conclusion The present nationwide survey, based on questionnaires, confirms an increased risk of early fractures in TS, especially in those without ovarian function and with a positive family history of fracture and osteoporosis. It thereby emphasizes the need for being vigilant with respect to BMD measurements in these patients.

Frequent association between MEN 2A and cutaneous lichen amyloidosis.

Abstract: Summary objective Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are genetic diseases due to activating mutations of the RET proto-oncogene. Affected patients develop medullary thyroid carcinoma (100%), in an isolated form (FMTC) or in association with phaeochromocytoma (30–50%), and primary hyperparathyroidism (10–20%) (MEN 2A). The presence of cutaneous lichen amyloidosis (CLA) has been anecdotally described in few families harbouring RET proto-oncogene mutation in codon 634. The aim of the study was to evaluate the incidence of CLA in MEN 2A/FMTC families. patients and design Ten MEN 2A/FMTC families were studied and RET gene mutations identified in all. Complete dermatological assessment was carried out in each family member. Skin biopsy for histological studies was performed in patients with CLA. results Among 10 MEN 2A/FMTC families, the presence of CLA was found only in patients belonging to the three families with MEN 2A and RET mutation in codon 634. Nine of 25 patients (36%) with codon 634 mutation presented CLA, though two of them did not show CLA skin lesions but the typical neurological pruritus in the upper back. In all patients, neurological pruritus was present since infancy as a precocious marker of the disorder. The dermatological study of patients with CLA skin lesions added further evidence that pruritus has a pivotal role in the development of CLA, the amyloid deposition being the consequence of repeated scratching. Light microscopy revealed orthokeratotic hyperkeratosis, with elongation of the rete ridges, rare intramalpighian apoptic keratinocytes and deposits of amorphous material in the superficial dermis. Examination under ultraviolet light showed thioflavin T-positive staining, confirming the presence of amyloid in the papillary dermis. The use of Capsaicin at the dilution of 0·025% had a mild efficacy on the cutaneous symptoms. conclusions Among the members of the three families with MEN 2A and RET 634 mutation, the incidence of CLA was 36%, a figure similar to that reported in the literature for phaeochromocytoma (30–50%) and even higher than that for hyperparathyroidism (10–20%). The present data confirm that CLA is linked to codon 634 RET mutations and is a precocious marker of the disorder.

Primary medical therapy for acromegaly.

Abstract: There is now considerable evidence that the clinical outcome in patients with acromegaly can be improved very substantially by means of better surgical expertise and effective medical therapies used in a flexible and innovative manner. Medical therapy alone in patients who have not undergone surgery or radiotherapy (primary medical therapy) offers the prospect of near normalisation of GH/IGF-I levels together with substantial tumour shrinkage in a significant number of patients.

Cortisol and the metabolic syndrome in South Asians

Abstract: The metabolic syndrome, a cluster of abnormalities including glucose intolerance, hypertension and dyslipidaemia (Reaven, 1988), has many similarities with Cushing’s syndrome which has led to the suggestion that a milder degree of hypothalamic–pituitary–adrenal (HPA) axis dysregulation may underlie this phenotype. This is supported by cross-sectional studies which show that individuals with raised blood pressure, glucose intolerance or other features of the metabolic syndrome have raised fasting plasma cortisol concentrations and increased reactivity of the HPA axis (Filipovsky et al., 1996; Phillips et al., 1998; Lee et al., 1999). The interplay between obesity and the HPA axis is complex. Tissue steroid metabolism, principally reactivation of cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in the liver, is altered in obese individuals leading to increased metabolic clearance of cortisol (Andrew et al., 1998; Stewart et al., 1999; Rask et al., 2001, 2002). As a result, although cortisol secretion is enhanced somewhat, circulating cortisol concentrations are generally normal or low in obese subjects. However, some studies suggest that a subset of individuals who maintain raised plasma cortisol concentrations in the face of obesity have a high prevalence of the metabolic syndrome. In these subjects, increased plasma cortisol concentrations or HPA reactivity add to the effect of adiposity in determining the risk of glucose intolerance, raised blood pressure and the metabolic syndrome (Phillips et al., 2000; Walker et al., 2000; Reynolds et al., 2001). South Asians have a high morbidity and mortality from coronary heart disease and the cardiovascular risk factors which comprise the metabolic syndrome are prevalent. Although South Asians have a relatively high proportion of fat, particularly visceral fat, across the body mass index (BMI) range compared with Caucasian populations, the increase in adiposity does not fully explain the high prevalence of the metabolic syndrome (McKeigue et al., 1991; Shelgikar et al., 1991; Banerji et al., 1999). A greater understanding of the mechanisms underlying this increased cardiovascular risk may allow new therapies to be developed. The role of glucocorticoids has not previously been investigated in this ethnic group. We have investigated the relationship between fasting 09·00 h cortisol concentration and cardiovascular risk factors in 509 adults from Mysore, South India to investigate the hypothesis that the high prevalence of the metabolic syndrome in South Asians is mediated by HPA axis hyperactivity.

The effects of soy protein containing isoflavones on lipids and indices of bone resorption in postmenopausal women.

Abstract: OBJECTIVE To assess the effect of a dietary soy protein supplement containing isoflavones on lipids and indices of bone resorption in postmenopausal women. DESIGN Placebo-controlled, double-blind, randomized study. PATIENTS One hundred and six postmenopausal women were randomized to dietary soy supplementation (n = 51) or placebo (n = 55) for 3 months, of which 78 were included in the final analysis. MEASUREMENTS Lipid profiles including total, low-density lipoprotein (LDL) and HDL cholesterol as well as triacylglycerol were measured. Pyridinoline and deoxypyridinoline were used as markers of bone resorption. Urinary isoflavone excretion was measured to assess compliance. RESULTS There was a significantly greater increase in urinary isoflavone excretion detected in the soy group compared to placebo. Lipid profiles improved with significant decreases in LDL cholesterol (-0.60 +/- 0.10 vs.-0.29 +/- 0.09 mmol/l, P < 0.05), triacylglycerol (-0.22 +/- 0.07 vs. +0.01 +/- 0.05 mmol/l, P < 0.005) and the LDL : HDL ratio (-0.32 +/- 0.10 vs. +0.20 +/- 0.10, P < 0.005) in the soy group compared to placebo. There were no significant differences between the soy and placebo groups for urinary excretion of pyridinoline (-3.8 +/- 3.1 vs.-0.8 +/- 3.1 nmol/mmolCr, P = 0.4) or deoxypyridinoline (-0.8 +/- 0.9 vs.-0.3 +/- 0.7 nmol/mmolCr, P = 0.4). CONCLUSIONS In postmenopausal women, dietary supplementation with soy protein containing isoflavones does not appear to have oestrogenic effects on markers of bone resorption. Soy protein favourably affected lipids; however, these effects (fall in triacylglycerol and no change in HDL) differ from those observed with oral oestrogen. These findings suggest that soy may not have biologically significant oestrogenic effects on bone resorption and we hypothesize that the lipid effects may be mediated, at least in part, through nonoestrogenic mechanisms.