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.

Efficacy and safety of three different cumulative doses of intravenous methylprednisolone for moderate to severe and active Graves' orbitopathy.

BACKGROUND: Optimal doses of i.v. glucocorticoids for Graves' orbitopathy (GO) are undefined. METHODS: We carried out a multicenter, randomized, double-blind trial to determine efficacy and safety of three doses of i.v. methylprednisolone in 159 patients with moderate to severe and active GO. Patients were randomized to receive a cumulative dose of 2.25, 4.98, or 7.47 g in 12 weekly infusions. Efficacy was evaluated objectively at 12 wk by blinded ophthalmologists and subjectively by blinded patients (using a GO specific quality of life questionnaire). Adverse events were recorded at each visit. RESULTS: Overall ophthalmic improvement was more common using 7.47 g (52%) than 4.98 g (35%; P = 0.03) or 2.25 g (28%; P = 0.01). Compared with lower doses, the high-dose regimen led to the most improvement in objective measurement of ocular motility and in the Clinical Activity Score. The Clinical Activity Score decreased in all groups and to the least extent with 2.25 g. Quality of life improved most in the 7.47-g group, although not reaching statistical significance. No significant differences occurred in exophthalmos, palpebral aperture, soft tissue changes, and subjective diplopia score. Dysthyroid optic neuropathy developed in several patients in all groups. Because of this, differences among the three groups were no longer apparent at the exploratory 24-wk visit. Major adverse events were slightly more frequent using the highest dose but occurred also using the lowest dose. Among patients whose GO improved at 12 wk, 33% in the 7.47-group, 21% in the 4.98-group, and 40% in the 2.25-group had relapsing orbitopathy after glucocorticoid withdrawal at the exploratory 24-wk visit. CONCLUSIONS: The 7.47-g dose provides short-term advantages over lower doses. However, this benefit is transient and associated with slightly greater toxicity. The use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This may suggest that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to most severe cases of GO.

Thyroid function and human reproductive health.

Via its interaction in several pathways, normal thyroid function is important to maintain normal reproduction. In both genders, changes in SHBG and sex steroids are a consistent feature associated with hyper- and hypothyroidism and were already reported many years ago. Male reproduction is adversely affected by both thyrotoxicosis and hypothyroidism. Erectile abnormalities have been reported. Thyrotoxicosis induces abnormalities in sperm motility, whereas hypothyroidism is associated with abnormalities in sperm morphology; the latter normalize when euthyroidism is reached. In females, thyrotoxicosis and hypothyroidism can cause menstrual disturbances. Thyrotoxicosis is associated mainly with hypomenorrhea and polymenorrhea, whereas hypothyroidism is associated mainly with oligomenorrhea. Thyroid dysfunction has also been linked to reduced fertility. Controlled ovarian hyperstimulation leads to important increases in estradiol, which in turn may have an adverse effect on thyroid hormones and TSH. When autoimmune thyroid disease is present, the impact of controlled ovarian hyperstimulation may become more severe, depending on preexisting thyroid abnormalities. Autoimmune thyroid disease is present in 5-20% of unselected pregnant women. Isolated hypothyroxinemia has been described in approximately 2% of pregnancies, without serum TSH elevation and in the absence of thyroid autoantibodies. Overt hypothyroidism has been associated with increased rates of spontaneous abortion, premature delivery and/or low birth weight, fetal distress in labor, and perhaps gestation-induced hypertension and placental abruption. The links between such obstetrical complications and subclinical hypothyroidism are less evident. Thyrotoxicosis during pregnancy is due to Graves' disease and gestational transient thyrotoxicosis. All antithyroid drugs cross the placenta and may potentially affect fetal thyroid function.

Outcome of orbital decompression for disfiguring proptosis in patients with Graves' orbitopathy using various surgical procedures.

AIM: To compare the outcome of various surgical approaches of orbital decompression in patients with Graves' orbitopathy (GO) receiving surgery for disfiguring proptosis. METHOD: Data forms and questionnaires from consecutive, euthyroid patients with inactive GO who had undergone orbital decompression for disfiguring proptosis in 11 European centres were analysed. RESULTS: Eighteen different (combinations of) approaches were used, the swinging eyelid approach being the most popular followed by the coronal and transconjunctival approaches. The average proptosis reduction for all decompressions was 5.0 (SD 2.1) mm. After three-wall decompression the proptosis reduction was significantly greater than after two-wall decompression. Additional fat removal resulted in greater proptosis reduction. Complications were rare, the most frequent being worsening of motility, occurring more frequently after coronal decompression. The average change in quality of life (QOL) in the appearance arm of the GO-QOL questionnaire was 20.5 (SD 24.8) points. CONCLUSIONS: In Europe, a wide range of surgical approaches is used to reduce disfiguring proptosis in patients with GO. The extent of proptosis reduction depends on the number of walls removed and whether or not fat is removed. Serious complications are infrequent. Worsening of ocular motility is still a major complication, but was rare in this series after the swinging eyelid approach.

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.

Resistin levels are normal in hypothyroidism and remain unchanged after attainment of euthyroidism: relationship with insulin levels and anthropometric parameters.

The aim of this controlled prospective study was to investigate resistin levels in hypothyroidism before and after restoration of euthyroidism and correlate the results with body weight (BW), body fat (BF), waist circumference (WC), body mass index (BMI) and serum insulin levels. Fifty-three hypothyroid patients with Hashimoto's disease (6 males, 47 females) and 30 controls matched for age, BMI and BF were investigated. Anthropometric parameters, resistin and insulin levels were measured. All patients were started on levothyroxine treatment and 4 to 5 months after initiation of treatment the investigations were repeated. Hypothyroid patients exhibited normal resistin values, which were no different from controls (mean+/-SD 7.4+/-4.0 vs 5.1+/-3.5 ng/ml, p=0.063). Normalization of circulating thyroid hormone levels produced no significant change in resistin levels (7.4+/-4.0 vs 6.8+/-4.2 ng/ml, p=ns) and post-treatment resistin levels did not differ from euthyroid controls. Furthermore, no gender difference was demonstrated in resistin levels either before (6.4+/-3.7 for males vs 7.6+/-4.1 ng/ml for females, p=ns) or after therapy (7.9+/-4.3 vs 6.7+/-4.3 ng/ml, for males and females respectively, p=ns), nor was there a difference in resistin levels in either sex induced by treatment of hypothyroidism (6.4+/-3.7 vs 7.9+/-4.3 ng/ml for males, p=ns, and 7.6+/-4.1 vs 6.7+/-4.3 ng/ml for females, p=ns). However, a small but significant difference in resistin levels was found between female patients and female controls (7.6+/-4.1 vs 5.0+/-4.0 ng/ml, p=0.047). Insulin levels and homeostasis model assessment insulin resistance (HOMA-IR) index did not differ before and after treatment in hypothyroid patients (13.0+/-10.2 vs 12.6+/-11.8 microU/ml, 22.7+/-1.4 vs 21.8+/-1.3, respectively, p=ns for both) or between patients and controls. In conclusion, our results demonstrate that resistin levels are normal in hypothyroidism and remain within normal range after attainment of euthyroidism. Resistin is not associated with serum insulin and HOMA-IR index, as well as BMI, BF, WC and BW.

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.

Recent developments in the medical treatment of thyroid eye disease.

No real new treatment has been developed in the last decade for thyroid eye disease (TED). Glucocorticoids (GC), orbital radiotherapy (OR) or a combination of both, are most frequently used in the treatment of TED for the iv immunosuppressive effects. However, we now have novel information regarding the when and how corticosteroids should be used. In general, the iv route of GC administration is preferable to the oral use. iv GC should be used at much lower doses than previously (4.5 to 6 g cumulative dose), possibly with a small dose of oral prednisone (or equivalent) in the interpulse period and for a few weeks after completion of iv treatment. Careful assessment of patients before treatment for identification of possible risk factors of liver toxicity is mandatory. Finally, monitoring of patients, particularly for liver function, is warranted during and after treatment. Although OR's effectiveness was disputed by a study few years ago, more recent studies have reconfirmed its beneficial role in TED and shown that it still has a positive role to play in patients with active TED. Finally, although Somatostatin-analogs (SM-as) gave the impression some years ago that might represent an effective weapon for TED management and initial, mostly uncontrolled and non-randomized trials with small number of patients supported this notion, newer randomized, double-blind studies with larger number of patients have not confirmed the first optimistic results. The question after that is if SM-as should be considered as a rubber bullet in the treatment of TED and we have to forget about them. The answer should be "no yet," especially in the light that the role of SM-as may be revitalized by the use of analogs with higher affinity for all somatostatin receptors subtypes. Such analogs are now available and under investigation in different diseases with very promising results.

Viral conjunctivitis interfering with the clinical activity score and management of thyroid ophthalmopathy.

INTRODUCTION: The management of Graves' ophthalmopathy is shared between endocrinologists and ophthalmologists. Assessment and treatment of the active inflammatory stage is based on the clinical activity and disease severity scores, often without detailed eye examination by the treating endocrinologist. MATERIALS AND METHODS: We report a case of acute viral keratoconjunctivitis occurring during immunosuppressive treatment for Graves' ophthalmopathy which masked the signs, symptoms and response to treatment of the orbitopathy, posing a differential diagnostic challenge. RESULTS: The apparent worsening of the ophthalmopathy and the increased clinical activity score led the treating endocrinologist to alter the management decisions. Ophthalmic examination confirmed the diagnosis of viral keratoconjunctivitis and immunosuppressive treatment was continued with significant final improvement of Graves' ophthalmopathy. DISCUSSION: Ocular surface conditions, unrecognised by the treating physician, may complicate the assessment of thyroid ophthalmopathy when detailed eye examination is not performed. The diagnostic challenge of Graves' ophthalmopathy requires a combined approach by an endocrinologist and an ophthalmologist working as a team.

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.

Gonadal effect of radiation from 131I in male patients with thyroid carcinoma.

The role of iodine-131 therapy in the management of differentiated thyroid carcinoma is well established. Because the spermatogonia are very sensitive to radiation, there is concern that large doses of the latter could result in azoospermia and permanent infertility. For patients treated with a single ablation dose, testicular function recovers within months and the risk of infertility is diminished. Gonadal damage may be cumulative in those requiring multiple administrations. In all young male patients, but especially in those with metastatic or pelvic disease or both, the long-term storage of semen should be addressed prior to therapy. Sperm banking should be considered in patients likely to be given cumulative doses greater than 14 GBq of 131I. However, the patient's threshold for sperm banking might be even lower than that.

Somatostatin analogs: a new tool for the management of Graves' ophthalmopathy.

Somatostatin (SM), a peptide inhibiting the release of GH, is present and plays an inhibitory role in the regulation of several organ systems in men and other species. Various SM analogs (SM-As) have been developed and used in clinical practice because the short half-life of SM makes it unsuitable for routine treatment. Recently it has been shown that SM-As might be of therapeutic value in the treatment of active thyroid ophthalmopathy. So far, 61 patients have been treated with octreotide and the results have been published in the literature. It was found that in 41 patients the drug had a beneficial effect. Ten patients were given lanreotide and 8 of those had a positive response, while 23 patients were treated with long-acting release octreotide and 16 improved. The exact mechanism of action of SM-As has not yet been fully clarified. One possible mechanism could be a direct inhibition of insulin-like growth factor (IGF)-I mediated effects. A second mechanism could be an inhibition of the release of lymphokines and inflammatory mediators from T-lympocytes. Finally, SM-As may act directly on target cells through specific cell surface receptors. With the introduction from Novartis of SOM-230, a compound which binds with high affinity to SM-receptors (SM-Rs) subtypes 1, 2, 3 and 5, with lower affinity to SM-Rs 4, and which has a very favorable T1/2 of nearly 24 h, a much better therapeutic outcome is expected. Thus, SM-As may provide a well-tolerated therapeutic alternative to corticosteroids. However, prospective placebo-controlled studies with large numbers of patients are needed before their role in the treatment of Graves' opthalmopathy is definitely established.

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.

Serum leptin values in relation to bone density and growth hormone-insulin like growth factors axis in healthy men.

A novel action of leptin on bone formation has recently been described in animals. However, in humans, studies provide data, that, are less conclusive. So far, few studies investigated the leptin-bone density association in males. Moreover, it has been suggested that GH, IGF-1 and IGFBP-3 may be major players in the hormonal or paracrine pathways that regulate bone cell metabolism. Also, leptin has been shown to modulate the GH/IGF pathway. The aim of this study was to clarify further this issue by investigating (a) the influence of serum levels of leptin, GH, IGF-1 and IGFBP-3 on bone mass in various skeletal sites and, (b), the relationship between leptin and the GH/IGF axis. 363 healthy individuals were investigated. BMD and serum leptin, GH, IGF-1 and IGFBP-3 serum levels were assessed. Our results indicate that 11% of healthy males had bone density with T scores

The cost of immunosuppressive therapies currently used in patients with thyroid eye disease.

Thyroid eye disease (TED) is an inflammatory condition of the orbit occurring in patients with autoimmune disease. In patients with mild TED, the most important therapeutic measure is reassurance. In severe cases, immunosuppressive therapy is the mainstay of treatment and around 10 immunosuppressive regimens have been suggested and used in such patients so far. The efficacy of these regimens varies according to the number of studies that have addressed these issues. "Response" to the treatment is also variably defined. However, to the best of our knowledge, no study has reported on the cost of immunosuppressive therapy in such patients. The aim of this study was mainly to provide information concerning the cost of different immunosuppressive regimens that patients with active thyroid ophthalmopathy undergo in different European countries. We have shown that the cheapest treatment is oral glucocorticoids (GC) and the most expensive is iv immunoglobulins. Cyclosporine is the second cheapest treatment. Radiotherapy plus oral GC have a cost between 850-3200 Euro; while SS analogues (SS-a) are expensive with a cost between 5000-10000 Euro. However, it is worth noting that the patients studied so far in this group were only few and most of them selected on a basis of a positive octreoscan, the cost of which has to be considered when choosing this type of treatment. Germany is by far the most expensive country as regards the costs of the main remedies, whereas Greece is the cheapest. Denmark is the most expensive country concerning radiotherapy, while Germany is the cheapest.

Thyroid disease and male reproductive function.

Despite the high prevalence of thyroid diseases in the general population, male reproductive function in patients with thyroid disease has been the subject of only a few studies. Hyperthyroidism appears to cause sperm abnormalities (mainly reduction in motility), which reverse after restoration of euthyroidism. Radioiodine therapy for hyperthyroidism or thyroid cancer may cause transient reductions in sperm count and motility, but there appears to be little risk of permanent effects provided that the cumulative dose is less than 14 MBq. The effects of hypothyroidism on male reproduction appear to be more subtle than those of hyperthyroidism and reversible. Severe, prolonged hypothyroidism in childhood may be associated with permanent abnormalities in gonadal function.

Growth hormone, insulin growth factor-1, and igf binding protein-3 axis relationship with bone mineral density among healthy men.

The aim of this study was to investigate serum levels of growth hormone (GH), insulin growth factor-I (IGF-I), and insulin growth factor binding protein-3 (IGFBP-3) in 363 healthy caucasian men with and without decreased bone density, who had never experienced fractures. Mean age was 51+/-8.7 years. Height and weight were measured and BMI was calculated using the formula weight (kg)/height (m(2)). Bone mineral density (BMD) was assessed: in 4 skeletal sites (lumbar spine [LS], femoral neck [FN], Ward's triangle [WT], and trochanter [T]) using dual-energy X-ray absorpsiometry (DEXA). After an overnight fasting, blood samples were taken at 8:00 a.m. Serum concentrations of GH, IGF-I, and IGFBP-3 were measured using the immunofunctional (GH) and IRMA (IGF-I and IGFBP-3) methods. The BMD at the 4 skeletal sites is expressed as mean value+/-SD in g/cm(2) and T score. Forty-four men (11%) had bone mineral density (BMD)<-2.5 SD (T score). Mean GH, IGF-I, and IGFBP-3 levels were 0.2+/-0.1, 186.1+/-177.3, and 4990+/-1460 ng/mL, respectively. There were no significant differences between men with normal BMD and men with reduced BMD concerning GH, IGF-I, and IGFBP-3 measurements. In normal men (319), mean GH, IGF-I, and IGFBP-3 levels were 0.4+/-0.1, 192+/-87, and 4960+/-1530 ng/mL, respectively. In the subgroup with reduced BMD (44), mean GH, IGF-I and IGFBP-3 levels were 0.2+/-0.1, 179+/-72 and 5230+/-1270 ng/mL, respectively. An age-dependent attenuation of GH, IGF-I, and IGFBP-3 levels was also found. No correlation was revealed between BMD and GH in the 4 skeletal sites tested. On the contrary, a positive correlation was established between BMD and IGF-I levels in 3 skeletal sites (LS, FN, T). The same was true between BMD and IGFBP-3 in 2 skeletal sites (LS, FN). In conclusion, 11% of Greek healthy males had decreased bone density. No fractures were demonstrated in any individuals. No significant differences were found between men with normal and reduced BMD, with regards to serum GH, IGF-I, and IGFBP-3, although these levels decreased with age. No correlation was found between BMD and GH levels in the 4 skeletal sites. A positive correlation was found between BMD and IGF-I levels in 3 skeletal sites and IGFBP-3 in 2 skeletal sites.

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.