Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

PURPOSE: Intravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves' orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention) and 24 (follow-up) weeks, particularly in patients initially unresponsive. METHODS: Our database (Bartalena et al. J Clin Endocrinol Metab 97:4454-4463, 10), comprising 159 patients given three different cumulative doses of methylprednisolone (2.25, 4.98, 7.47 g) was analyzed, pooling data for analyses. Responses at 6 weeks were compared with those at 12 and 24 weeks using three outcomes: overall ophthalmic involvement [composite index (CI)]; quality of life (QoL); Clinical Activity Score (CAS). Responses were classified as "Improved", "Unchanged", "Deteriorated", compared to baseline. RESULTS: Deteriorated patients at 6 weeks for CI (n = 8) remained in the same category at 12 weeks and 7/8 at 24 weeks. Improved patients at 6 weeks for CI (n = 51) remained in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively. Unchanged patients at 6 weeks (n = 100) eventually improved in 28% of cases (CI), 58% (CAS), 32% (QoL). There was no glucocorticoid dose-dependent difference in the influence of early response on later outcomes. CONCLUSIONS: Patients who deteriorate at 6 weeks after ivGCs are unlikely to benefit from continuing ivGCs. Patients unresponsive at 6 weeks still have a significant possibility of improvement later. Accordingly, they may continue ivGC treatment, or, alternatively, possibly stop ivGCs and be switched to a second-line treatment.

Psychological implications of Graves' orbitopathy.

Patients with thyroid eye disease, Graves' orbitopathy (GO), often appear distressed and it is likely that features of the condition such as disturbances in visual function, orbital discomfort and alterations in facial appearance can impart significant psychological morbidity upon the patient, which in turn can be detrimental to their quality of life. When considering the psychological impact of GO, two elements of the disease are important. The disfiguring changes to the eyes and face can have a direct effect upon psychological health, while physical aspects of the disease such as altered visual acuity, diplopia, orbital pain and lacrimation may influence psychological function as a secondary phenomenon, due to interference with daily living. Evidence appears to confirm the anecdotal impression of many clinicians dealing with GO patients that the prevalence of psychological morbidity in this patient group is high. A 'biopsychosocial' approach to care that addresses biological and psychosocial functioning as major determinants of health is an appropriate strategy when treating patients with GO.

A questionnaire survey on the management of Graves' orbitopathy in Europe.

OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.

Childhood Graves' ophthalmopathy: results of a European questionnaire study.

OBJECTIVE: Evaluation of the frequency of Graves' ophthalmopathy (GO) and its management in children and adolescents up to 18 years old with Graves' hyperthyroidism. STUDY DESIGN: This was a questionnaire study (QS) among members of the European Thyroid Association and the European Society for Paediatric Endocrinology. Approximately 300 QS were sent to members with electronic addresses and 110 QS were returned from 25 countries: 52 respondents said they had no experience with Graves' disease in this age group, but 67 respondents (23 paediatric and 44 adult endocrinologists) completed the QS. RESULTS: Out of 1963 patients with juvenile Graves' hyperthyroidism seen by respondents in the last 10 years, 641 (33%) had GO; about one-third of GO cases were < or =10 years old, and two-thirds were 11-18 years old. The prevalences of GO among juvenile Graves' hyperthyroidism were 36.6, 27.3 and 25.9% in countries in which the smoking prevalence among teenagers was > or =25, 20-25 and <20% respectively (P < 0.0001 by chi(2) test). When confronted with the standard case of a 13-year-old girl with Graves' hyperthyroidism and moderately severe active GO, the diagnostic approach included on average 4.9 biochemical tests (TSH, free thyroxine (FT(4)) and TSH.R-Ab, 100-88% of respondents) and 2.4 specific investigations (thyroid ultrasound by 69%, orthopsy/visual fields/visual acuity by 64% and orbital magnetic resonance imaging or computed tomography by 63%). Antithyroid drugs were the treatment of choice for 94% of respondents; 70% recommended a wait-and-see policy and 28% corticosteroids for the co-existing GO. In variants of the standard case, a younger age did not affect therapeutic approach very much. Recurrent hyperthyroidism would still be treated with antithyroid drugs by 66%, and with (131)I by 25%. Worsening of GO or active GO when euthyroid would convince about two-thirds of respondents to initiate treatment of GO, preferably with steroids. CONCLUSION: GO occurs in 33% of patients with juvenile Graves' hyperthyroidism; its prevalence is higher in countries with a higher prevalence of smoking among teenagers. The diagnostic approach to the standard case of a 13-year-old with Graves' hyperthyroidism and moderately severe active GO involves on average five biochemical tests; thyroid as well as orbital imaging is done in 84% of cases. Antithyroid drugs remain the treatment of choice for 94% of respondents, and even so in case of recurrences (66%). For GO, 70% recommend a wait-and-see policy; intervention, preferably with steroids, is advocated by two-thirds of respondents in cases of worsening or still-active eye disease despite euthyroidism.

A prospective controlled study of the impact of hyperthyroidism on reproductive function in males.

The aim of this prospective controlled study was to ascertain the effect of hyperthyroidism on sperm quality and composition. We studied 23 thyrotoxic male patients, aged 43.8 +/- 2.4 yr (mean +/- SEM), and 15 healthy male controls of approximately the same age (42.2 +/- 2.2 yr). Two semen analyses at intervals of 2-3 wk were obtained before and about 5 months after euthyroidism was achieved either by methimazole alone (14 patients) or (131)I plus methimazole (9 patients). Total fructose, zinc (Zn), and magnesium (Mg) were also measured in seminal plasma in 16 patients, because 7 had semen volume less than 2 ml. In the control group semen analysis was performed only once. Mean (+/-SEM) semen volume was within normal range both in patients (3.3 +/- 0.2 ml) and controls (3.5 +/- 0.4 ml; P = NS). Mean sperm density was lower in patients, although the difference compared with controls did not reach statistical significance (35.7 +/- 5.3 vs. 51.5 +/- 6.1 x 10(6)/ml; P = 0.062). The same was found with sperm morphology (68 +/- 7% vs. 78 +/- 8%; P = NS). Finally, mean motility was lower in thyrotoxic males than in controls (28 +/- 8% vs. 57 +/- 7%; P < 0.01). After treatment, sperm density and motility improved [35.7 +/- 5.3 vs. 43.3 +/- 6.5 x 10(6)/ml (P = NS) and 28 +/- 8% vs. 45 +/- 7% (P < 0.05), respectively], but sperm morphology did not change (68 +/- 7% vs. 70 +/- 6%; P = NS). Mean values for fructose, Zn, and Mg did not differ between controls and patients either before or after achievement of euthyroidism [9.2 +/- 0.7, 3.0 +/- 0.5, and 4.2 +/- 0.7 nmol/liter vs. 8.6 +/- 0.9, 3.0 +/- 0.5, and 4.7 +/- 0.8 nmol/liter (patients before) and 9.1 +/- 0.7, 3.1 +/- 0.6, and 4.5 +/- 0.9 nmol/liter (patients after treatment) for fructose, Zn, and Mg, respectively]. Moreover, according to the treatment given, no statistically significant differences were found before or after treatment. Finally, seminal plasma fructose, Zn, and Mg levels did not correlate with sperm parameters or with pretreatment thyroid hormone levels. In conclusion, the results of our study indicate that male patients with hyperthyroidism have abnormalities in seminal parameters, mainly sperm motility. These abnormalities improve or normalize when the patients become euthyroid. Restoration of sperm parameters was independent of the treatment provided for the hyperthyroid syndrome. Moreover, seminal plasma elements, such as fructose, Zn, and Mg, did not correlate with sperm density, motility, or morphology.

Free and total insulin-like growth factor (IGF)-I, -II, and IGF binding protein-1, -2, and -3 serum levels in patients with active thyroid eye disease.

To determine whether serum levels of total (T) and free (F) IGF-I and -II and IGF binding protein (IGFBP),-1, -2, and -3 are normal in euthyroid patients with Graves' disease and active thyroid ophthalmopathy, we investigated the above-mentioned parameters in 21 patients (11 male, 10 female) aged 50.8 +/- 11.8 yr (range 35-70) and 19 healthy individuals matched for age, gender, and body mass index. All patients had active thyroid eye disease (TED) with clinical activity scores > or = 4 and positive orbital octreoscan in both eyes. Serum T and F IGF-I and IGF-II were determined using noncompetitive time-resolved monoclonal immunofluorometric assays, IGFBP-1 was determined by an in-house RIA, IGFBP-2 by a novel in-house time-resolved immunofluorometric assay, whereas IGFBP-3 by an immunoradiometric assay. All data are expressed as mean +/- SD. Our results show that T and F IGF-I, -II, and IGFBP-1, -2, and -3 levels in patients were similar to controls and did not show any significant difference. Specifically, mean T IGF-I for patients group was 131 (61), F IGF-I was 0.47 (0.16), T IGF-II was 1056 (300), F IGF-II was 1.45 (0.54), IGFBP-1 was 33 (14), IGFBP-2 was 848 (377), and finally IGFBP-3 was 3953 (1422). For controls, mean T IGF-I was 146 (51), F IGF-I was 0.85 (0.43), T IGF-II was 939 (197), F IGF-II was 1.53 (0.53), IGFBP-1 was 44 (24), IGFBP-2 was 764 (316) and finally IGFBP-3 was 3721 (1017). Furthermore, no statistically differences emerged in the ratio between molar weights of T IGF-I/IGFBP-3 and T IGF-II/IGFBP-3, as well as to the F/T IGF-I and F/T IGF-II. Finally, no relationship was found between the levels of the above-mentioned parameters and clinical activity scores, octreoscan scores, and thyroid hormones. Our data demonstrate for the first time that serum levels of IGFs (including free fractions) and IGFBPs are not increased in euthyroid Graves' patients with active TED. The increased IGF levels in retrobulbar tissues previously described, appear to be independent of serum IGFs concentration and probably represent autocrine and/or paracrine activity.

Treatment of juvenile Graves' disease and its ophthalmic complication: the 'European way'.

Three treatment modalities are available for Graves' disease: antithyroid drugs, surgery and radioactive iodine (RAI). None has been shown to be ideal or superior to the others. There are wide differences between individual physicians and between the physicians in different countries on the optional treatment for childhood hyperthyroidism. While antithyroid drugs remain the initial treatment of choice in almost all the medical centers in Europe, with surgery being used mainly to deal with antithyroid failures, radioiodine is preferred by only a small percentage of physicians for this group of patients. In the USA, on the contrary, radioiodine treatment of thyrotoxicosis in children has strong advocates, who emphasize the safety, simplicity and economic advantages of iodine-131 ablation, which should be considered more commonly in children. Until now, the available data have shown no significant increase in thyroid neoplasia, gonadal injury or congenital abnormalities in the offspring of older children and adults receiving RAI for thyrotoxicosis. Given the considerable increase in the risk of thyroid cancer in young children exposed to external radiation, it has been hypothesized that there may be a small increase in the risk of thyroid cancer in young children treated with RAI. Until long-term data on safety are available, specifically for young children, differences between the physicians in different countries will remain.

The role of octreoscan in thyroid eye disease.

Until recently there was no imaging technique available which could demonstrate pathological changes in orbital tissues and could be regarded as a reliable measure of inflammation in thyroid eye disease (TED). Pentetreotide (a synthetic derivative of somatostatin) labelled with 111In has been used to localize tumours which possess surface or membrane receptors for somatostatin in vivo using a gamma camera (1). This technique visualizes somatostatin receptors in endocrine-related tumours in vivo and predicts the inhibitory effect of the somatostatin analogue octreotide on hormone secretion by the tumours (1). By applying 111In-DTPA-d-Phe octreotide scintigraphy (octreoscan), accumulation of the radionuclide was also detected in both the thyroid and orbit of patients with Graves' disease (2-4). If peak activity in the orbit 5h after injection of radiolabelled octreotide is set at 100%, a decrease to 40+/-4% is found at 24h, significantly different from the decrease in blood pool radioactivity, which is 15+/-4% at 24h. Accumulation of the radionuclide is most probably due to the presence in the orbital tissue of activated lymphocytes bearing somatostatin receptors (5). Alternative explanations are binding to receptors on other cell types (e.g. myoblasts, fibroblasts or endothelial cells) or local blood pooling due to venous stasis by the autoimmune orbital inflammation.

Immunosuppressive therapy in patients with thyroid eye disease: an overview of current concepts.

Thyroid eye disease (TED) is a debilitating disease impairing the quality of life of affected patients. Treatment is often not satisfactory. This review summarizes the existing literature and discusses the most widely used forms of treatment for TED such as glucocorticoids (GCs), and other immunosuppressive agents. GCs are the most commonly used treatment in patients with TED. Other immunosuppressive agents such as cyclosporin A, azathioprin, cyclophosphamide and ciamexone have been used, but the results are modest at best and indicate an unfavorable benefit-risk relationship. Limited experience indicates that methotrexate may be effective even in patients with refractory TED. Somatostatin analogs, octreotide and lanreotide, may provide a valuable, although costly, therapeutic alternative to GCs. Orbital radiotherapy has been used in the management of TED for almost 60 years. However, its beneficial effects have been questioned recently by several studies, the details of which have not yet been published. Other studies have argued in favor of orbital radiotherapy; however, the benefits appear to be limited to improvement of extraocular muscle dysfunction.

Lanreotide in the treatment of patients with thyroid eye disease.

Octreotide, a potent synthetic somatostatin (SM) analogue, was recently evaluated and found to have a beneficial effect in thyroid eye disease (TED), mostly in those patients with a positive Octreoscan-111. Lanreotide (LRT; Somatuline-Ipsen), a new SM long-acting analogue, is more active than natural SM and shows a much longer duration of action. The aim of the present preliminary study was to evaluate the therapeutic effect of LRT in the treatment of TED. Five patients, three males and two females, mean age 50.6 +/- 7.6 S.D. (45-64) years, all with severe symptoms of TED were studied. A similar number of patients, matched for age, sex and severity of ophthalmopathy served as controls. All the patients and controls were investigated with orbital scintigraphy using 111 In DTPA-D-Phe1-octreotide (Octreoscan-111) and selected on the basis of positive octreoscan. The NOSPECS system, as adapted by Donaldson et al. (Journal of Clinical Endocrinology and Metabolism 1973 37 276-285) and a disease activity score, as proposed recently by an International Workshop, have been followed in this study in order to evaluate the response to treatment. The five patients who comprised the treatment group received 0.04 g LRT i.m. once every 2 weeks over a period of 3 months, after which the Octreoscan-111 was repeated. The control patients were given an injection of water i.m., also once every 2 weeks for 3 months, after which they were evaluated clinically. No Octreoscan-111 was performed in the controls. All patients and controls were evaluated by the same physician, who was unaware of the type of treatment used. A decrease in the NOSPECS score and the clinical activity score was regarded as a positive response, while no change or an increase in the NOSPECS score along with no clinical improvement was regarded as a negative response. After 3 months of treatment with LRT, four patients showed a statistically significant improvement in ophthalmopathy in both eyes and one in one eye. Three of the control patients with TED did not show any change, one showed a minor improvement in one eye and no change in the other and one showed deterioration in both eyes. An interesting finding was that orbital Octreoscan-111 activity was absent in all the patients after LRT treatment. In conclusion, these preliminary results show that LRT has a beneficial effect on patients with TED, and that since it has to be given only once every 2 weeks, it is probably superior to any other form of SM treatment. However, as the number of patients was small, further studies are needed to confirm our results.

Leptin levels in women with polycystic ovary syndrome before and after treatment with diazoxide.

Leptin, a product of the ob gene, is a 16 kDa protein which is produced by adipocytes. In humans, obesity is a common finding in women with polycystic ovary syndrome (PCOS). The role, however, of leptin in PCOS is not clear. Some studies have reported increased levels of leptin in PCOS, while others report that they are normal. Also, insulin resistance is a common finding in PCOS. The aim of this study was to investigate further the role of insulin in leptin secretion in patients with PCOS by treating them for 10 days with diazoxide, an insulin-reducing compound. Eight women with PCOS, mean age 22.1 +/- 2.7 years, with mean body mass index (BMI) 28.4 +/- 5.7kg/m2, were studied. An oral glucose tolerance test (OGTT) was performed in all women and blood samples were taken before and at 30, 60, 90, 120 and 150 min after the administration of glucose. Glucose, insulin, leptin, free testosterone, delta4 androstenedione, sex hormone binding globulin (SHBG), LH, FSH, IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3) were measured in the sera taken before the administration of glucose, while glucose and insulin levels were measured in all samples which were collected after the administration of glucose. Diazoxide 300 mg daily was given to all women starting after the end of the OGTT for 10 days. A second OGTT was performed the day after the discontinuation of the diazoxide treatment. The same hormonal and biochemical parameters were also measured in all patients during the second OGTT. After the administration of diazoxide a reduction in sum insulin (262 +/- 147 vs 679 +/- 341 microU/ml. P<().01), leptin (18.5 +/- 10.6 vs 24.2 +/- 10.2 ng/ml, P<0.01), free testosterone (3.0 +/- 1.9 vs 5.1 +/- 1.9 pg/ml, P<0.01), delta4 androstenedione (3.8 +/- 1.9 vs 5.7 +/- 2.0 ng/ml, P<0.01) and IGF-I (219.5 +/- 69.2 vs 314.5 +/- 82.3 ng/ml, P<0.01) levels was observed. Serum SHBG (38.8 +/- 16.8 vs 27.8 +/- 12.1 nmol/l, P<0.01) and sum glucose levels (994.1 +/- 252.7 vs 711.1 +/- 166.1 mg/dl, P<0.05) were increased while IGFBP-3 (3.96 +/- 2.49 vs 3.75 +/- 2.24mg/l), FSH (6.2 +/- 1.8 vs 6.0 +/- 2.5 mU/l) and LH (18.9 +/- 6.7 vs 21.4 +/- 6.7 mU/l) concentrations did not change significantly. A significant positive correlation was found between serum leptin and BMI values before and after administration of diazoxide as well as between leptin, insulin and IGFBP-3 values. Also, sum insulin values correlated significantly with BMI. However, when multiple regression analysis was used this correlation was eliminated except that between leptin and BMI. This was most probably due to the small number of cases. The mechanism of the reduction of leptin levels is unclear. However, it is suggested that the concomitant decrease of insulin levels may play a role.

Idiopathic juvenile osteoporosis.

Osteoporosis in childhood is uncommon, and it may be secondary to a spectrum of diverse conditions. When such causes have been excluded, some patients remain who have a congenital disease (osteoporosis imperfecta) or a disease in which the etiology is obscure, called idiopathic juvenile osteoporosis (IJO). The cause of IJO is unknown, and the diagnosis is based both on the exclusion of other diseases and on its own positive fractures. The basic strategy of treatment is to protect the spine until remission occurs. Sex steroids are contraindicated. Bisphosphonates, calcitriol, fluoride, and calcitonin have been administered therapeuticlly, but the results were equivocal. Usually the disease remits by itself.

Thyroid disease and female reproduction.

OBJECTIVE: To review the menstrual function and fertility in thyroid disease, mainly in hyperthyroidism and hypothyroidism. Also to register the consequences of (131)I therapy, which is used widely in the treatment of Graves' disease and thyroid cancer, on subsequent pregnancies and on fertility in these patients. DESIGN: A MEDLINE computer search was used to identify relevant studies. The type of menstrual disturbances and the status of fertility were recorded from all the studies found. Also, the fertility and genetic hazard of female patients with Graves' disease and thyroid cancer who were treated with (131)I were registered. RESULT(S): Both hyperthyroidism and hypothyroidism may result in menstrual disturbances. Menstrual abnormalities are less common now than in previous series. In a recent study, we found that only 21.5% of 214 thyrotoxic patients had some type of menstrual disturbance, compared to 50 to 60% in some older series. The most common manifestations are hypomenorrhea and oligomenorrhea. According to the results of endometrial biopsies, most thyrotoxic women remain ovulatory. Moreover, the genetic hazard incident to radioiodine therapy in Graves' disease and thyroid carcinoma is very small; exposure to (131)I does not cause reduced fecundity, and the risk of loss of fertility is not a contraindication for its use in these patients. mIn hypothyroidism, the frequency of menstrual irregularities has very recently been reported to be 23.4% among 171 hypothyroid patients studied. This is much less than that reported in previous studies, which showed that 50 to 70% of hypothyroid female patients had menstrual abnormalities. The most common manifestation is oligomenorrhea. Severe hypothyroidism is commonly associated with failure of ovulation. Ovulation and conception can occur in mild hypothyroidism. These pregnancies are, however, often associated with abortions, stillbirths, or prematurity. The latter may be of greater clinical importance in infertile women with unexplained infertility. CONCLUSION(S): These new data, mainly concerning menstrual abnormalities in hyperthyroidism and hypothyroidism, are inconsistent with what is generally believed and written in the classic thyroid textbooks and indicate that such opinions should be revised.

Somatostatin analogues in the treatment of thyroid eye disease.

Recent studies have shown successful therapy with the long-acting somatostatin (SM) analogues octreotide and lanreotide in patients with thyroid eye disease (TED). In one such study it was also found that response to low-dose octreotide treatment (300 microg) in these patients was correctly predicted by [111In-DTPA-D-Phe1]-octreotide scintigraphy and concluded that this parameter should be used as a predictive test of the effectiveness of treatment with nonradioactive octreotide. It has also been suggested that octreoscan-111 may be seen as a parameter of disease activity in TED. However, it remains to be clarified whether octreoscan-111 predicts the therapeutic outcome better than the clinical activity score, or magnetic resonance imaging (MRI) or finally measurement of glucosaminoglycan (GAG) in the plasma and/or urine. The exact mechanism of action of SM analogues has not yet been fully clarified. Three explanations may be offered. First, SM suppresses insulin-like growth factor 1 (IGF-1) activity and inhibits IGF-1-mediated effects. A second possible mechanism could be the direct inhibition of the release of cytokines from T-lymphocytes, and finally, SM analogues may act on target cells through specific cell surface receptors. In view of the encouraging therapeutic results reported thus far in several studies, SM analogues may provide a valuable therapeutic alternative to corticosteroids, especially in patients who cannot tolerate the latter. However, further prospective, placebo-controlled studies with a large number of patients are needed before we can reach final conclusions.

Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment.

The aim of this prospective, follow-up study was to examine the influence of overt hypothyroidism (OHP) and subclinical (SHP), before and during thyroxine (T4) treatment, on lipoprotein(a) [Lp(a)], other lipoproteins, and apolipoproteins. Twenty-four patients (17 females, 7 males) with OHP, aged 54 +/- 11.1 years (group A) and 23 patients (females) with SHP aged 50.1 +/- 13.2 years (group B) were evaluated and compared to 34 and 38 controls, respectively. All patients received T4 therapy in a stepwise fashion until euthyroidism was reached. Thyrotropin (TSH), free thyroxine (FT4), and total triiodothyronine (TT3) levels were measured before T4 therapy and repeatedly every 4 weeks after the initiation of treatment until the euthyroid state was reached. Levels of Lp(a), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), apolipoprotein A1 (apoA1) and apolipoprotein B (apoB) were measured before and 4 months after the achievement of euthyroidism. Additionally, body mass index (BMI) was also evaluated. We found that in OHP patients, levels of TC, LDLc, and apoB were elevated before treatment and decreased significantly after the return to the euthyroid state. BMI and levels of triglycerides also decreased significantly; Lp(a) was higher in OHP patients in comparison with controls and decreased significantly by 14.56% (25.29% in men and 10.34% in women) during T4 treatment. In SHP patients, levels of all common lipoproteins, apolipoproteins, and Lp(a) did not differ significantly from controls before treatment and did not change after the euthyroid stage was reached. It is concluded that in overt hypothyroidism, Lp(a) levels and most of the lipoproteins were elevated before treatment and decreased significantly. In subclinical hypothyroidism, lipoproteins and Lp(a) levels were normal at baseline and did not change during treatment.

Somatostatin receptor scintigraphy before and after treatment with somatostatin analogues in patients with thyroid eye disease.

Octreotide, a potent synthetic long-acting somatostatin analogue, has been shown to have a beneficial effect in thyroid eye disease (TED). Orbital scintigraphy using ocetreoscan-111 is a useful study, which can be used to visualize somatostatin-receptor-bearing cells and also to select patients who might benefit from octreotide therapy. One major limitation of this therapy is that the drug must be administered parenterally and used several times daily. Lanreotide, a new somatostatin analogue, has a much longer duration of action in comparison with octreotide, and has recently been found to have a beneficial effect in the treatment of thyroid eye disease. The aim of this study was to investigate the orbital Indium-111-pentetreotide activity after treatment with octreotide and lanreotide in patients with thyroid ophthalmopathy. Fourteen patients were studied. 12 with bilateral and 2 with unilateral thyroid eye disease, (10 females and 4 males) and all with moderately severe symptoms of ophthalmopathy. All were treated with antithyroid drugs and were euthyroid at the time of the study. All patients were investigated with orbital scintigraphy using octreoscan-111 and selected for study on the basis of a positive octreoscan. Five patients received 30 mg lanreotide intramuscularly once every 2 weeks over a period of 3 months, and 5 patients received octreotide 100 microg subcutaneously thrice daily for 3 months. Four patients served as controls and received no treatment. The octreoscan-111 scintigraphy was repeated in all patients 3 months after the first examination. The NOSPECS classification and the clinical activity score (CAS) of thyroid ophthalmopathy were also evaluated before and 3 months after the initiation of treatment. All patients who received treatment had a negative follow-up octreoscan while controls had a positive octreoscan. NOSPECS score and CAS were improved with treatment, but unchanged in control patients. The reduced uptake of octreoscan may be the result of blocking of somatostatin receptors, or reduction in receptor-expressing tissues, downregulation of somatostatin receptors in target tissues, or a combination of these factors.

Serum levels of tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and soluble interleukin-1 receptor antagonist in patients with thyroid eye disease undergoing treatment with somatostatin analogues.

The aim of this prospective, randomized study was to investigate the serum levels of tumor necrosis factor-alpha (TNF-alpha), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble interleukin-1 receptor antagonist (sIL-1RA) in patients with thyroid eye disease (TED) before and 1 and 3 months after treatment with somatostatin analogues (SM-a). Thirty patients, all with signs and symptoms of TED, were studied. Twenty-two patients (13 females) had active eye disease with a clinical activity score (CAS) > or = 4 (patients with active disease [PA]) and 8 patients (5 females) had inactive TED with CAS < or = 3 (patients with inactive disease [PI]). All PA patients had a positive orbital octreoscan, whereas PI patients had a negative one. Fifteen patients from the PA group were selected randomly and received SM-a (PA-S subgroup), while the remaining 7 patients were used as control subgroup (PA-C), received neither therapy, nor placebo. From the 15 patients who received SM-a (PA-S), 6 received octreotide (OCT) and 9 lanreotide (LRT). TED was reevaluated using the CAS 1 and 3 months after the initiation of SM-a treatment. Ten healthy individuals (6 females) were used as controls (group C). We found an increase in the basal levels of TNF-alpha (14.2 +/- 7.1 pg/mL), sICAM-1 (809.1 +/- 167.0 ng/mL), and sIL-1RA (542.1 +/- 259.0 pg/mL) in PA patients as a total group compared with the PI (1.6 +/- 1.9, 676.8 +/- 73.4, 267.6 +/- 152.8, respectively) group and C (1.9 +/- 1.4, 598.0 +/- 126.2, 258.6 +/- 155.1, respectively). The basal levels of TNF-alpha (13.3 +/- 8.3 pg/mL) and sIL-1RA (533.7 +/- 308.9 pg/mL) in PA-S as well as in PA-C (16.0 +/- 2.9, 560.2 +/- 107.3, respectively) subgroups were also increased compared with PI patients and C (1.9 +/- 1.4 and 258.6 +/- 155.1, respectively). The same was true for sICAM-1 when baseline levels compared with C (817.1 +/- 187.3 and 791.9 +/- 123.5, respectively vs. 598.0 +/- 126.2 ng/mL). After SM-a, serum levels of sICAM-1 and sVCAM-1 were decreased significantly 1 (781.2 +/- 205.9, 1,193.5 +/- 511.8 ng/mL) and 3 months (786.8 +/- 199.6, 1,122.1 +/- 225.3 ng/mL) after the initiation of treatment. In conclusion, serum levels of TNF-a, sICAM-1, and sIL-1RA were elevated in patients with active TED compared to controls. Furthermore, sICAM-1 and sVICAM-1 levels declined during the treatment with SM-a in patients with active TED.

Oestrogen action on bone cells.

Sex steroids have an important impact on bone physiology. Oestrogen (E) appears to be the most important sex steroid in preventing osteoporosis in women. Despite the overwhelming evidence that oestrogens modulate bone growth and turnover in vivo, oestrogen receptors (ER) were detected only recently. Two forms of ER have been discovered so far, ERalpha and ERbeta. Both have been detected in osteoblasts and osteoclasts as well. A number of growth factors and cytokines appear to modulate bone resorption in vitro and in vivo. Among others, interleukin-1 and -6 and tumor necrosis factor alpha and beta were found to be extremely potent stimulators of bone resorption. Binding of different cytokines to their receptors in osteoblasts result in the release of soluble factors that act directly on osteoclasts to modulate their recruitment or activity. Thus, E, apart from the direct regulation of osteoclasts, which it achieves through its receptors, can inhibit the release of osteoclast stimulatory factors or enhance the release of osteoclast inhibitory factors. In general, E is an inhibitor of bone resorption that decreases both osteoclast numbers and activity. Recently, it has also been shown that it promotes apoptosis. Moreover, it also has anabolic effects on osteoblasts. However, E action on osteoclasts is superior in comparison with that on osteoblasts. Recent data have shown that transforming growth factor beta (TGFbeta) mediates the actions of E in bone. Following the example of raloxifene it may be proved that the role of TGFbeta in the actions of E in bone is central and has not only academic interest. More data are needed to elucidate this issue. Finally, recent data suggest the importance of E for bone maturation and development of peak bone mass in men. It seems likely that both E and androgens are required for the growth and maintenance of the adult male skeleton.

Prevalence and trends in overweight and obesity among children and adolescents in Thessaloniki, Greece.

Obesity is the most prevalent nutrition-related problem in Western societies. Childhood obesity is rapidly emerging as a global epidemic that will have profound public health consequences, as overweight children become overweight adults. The aim of this study was to investigate the prevalence of overweight and obesity among children and adolescents in the city of Thessaloniki, and evaluate the trends in Greece by comparing our results to those of other cross-sectional studies. Data concerning the height and weight of 2,458 schoolchildren aged 6 to 17 years (1,226 6-10 years, 1,232 11-17 years) of 27 primary and secondary public schools were collected. BMI was calculated from the two measurements. In the analyses, the estimations of the prevalence of overweight and obesity are based on recently established international BMI percentile curves and cut-off points from 2-18 years. To investigate the secular trends in obesity in Greece, data of schoolchildren from four successive surveys were used. In the younger group (6-10 yr), the prevalence of overweight and obesity were 25.3% and 5.6%, while for adolescents (11-17 yr) they were 19.0% and 2.6%, respectively. The prevalence was 25.9% and 5.1% for all males, and 19.1% and 3.2% for all females, respectively. As far as trends are concerned, an increase of BMI was found among males when the results of our survey were compared with those of the previous three. However, the trends for girls are different. An increase was found when the results of our study were compared with 1942. A decrease of BMI at most ages was found when the results of our study were compared with those of the 1982 survey, while an increase was recorded only for younger girls below 13 years compared to the 1984-5 study. This study demonstrates that the prevalence of overweight and obesity among schoolchildren is 22.2% and 4.1%, respectively, and has been increasing in the last decades, especially among boys.

Determinants of body mass index in Greek children and adolescents.

The aim of this study was to investigate the determinants of body mass index (BMI) among Greek children and adolescents, such as parental age and BMI, number of family members in the household, parents' educational status and occupation, physical activity and hours of television viewing and playing computer games by children per day. This cross-sectional study included 2,495 children aged 6-17 years from primary and high schools of Thessaloniki, capital of Northern Greece. Data were collected by questionnaires concerning age, height and weight of the parents, number of family members, and socioeconomic status as determined by occupation and educational status of the parents. Our results revealed that overweight in Greek children and adolescents is influenced positively by several determinant factors, such as parental age and obesity, hours of television viewing, and negatively by a high parental educational level. No significant association was found between children's BMI and physical activity. Intervention and prevention measures should be targeted at the reduction of sedentary activities, especially television viewing, and promotion of physical activity. These measures should be directed at families that are affected and/or concerned with obesity.