[New immunomodulators in treatment of Graves'ophtalmopathy]. / Les nouveaux immunomodulateurs dans le traitement de l'ophtalmopathie basedowienne.

Treatment of severe Graves'ophtalmopathy (GO) is a complex therapeutic challenge and spite any efforts, about one third of patients are disappointed with the outcome of treatment. Intravenous glucocorticoids (GCIV), orbital radiotherapy, or the combination of both are most frequently used for their immunosuppressive effects. The anti-CD 20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophtalmopathy (TAO). A preliminary study in nine patients with TAO treated with RTX and twenty patients treated with GCIV was reported by Salvi and al. All patients attained peripheral B-cell depletion after the first RTX infusion. At the end of follow-up, clinical activity score values decreased more significantly compared with GCIV. Proptosis and the degree of inflammation decrease significantly in response to RTX. Relapse of active TAO are not observed in patients treated with RTX but occurred in 10 % of those treated with GCIV. If these results are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.

[Thyroid hormone analogs: an important biological supply and new therapeutic possibilities]. / Les analogues des hormones thyroïdiennes : un apport biologique important et de nouvelles possibilités thérapeutiques.

Thyroid hormones [predominantly 3, 5, 3 -I- iodothyronine (T3)] regulate cholesterol and lipoprotein metabolism but cardiac effects restrict their use as hypolipidemic drugs. New molecules have been developped which target specifically the thyroid hormone receptor ss, predominant isoform in liver. The first thyroid hormone agonist, called GC1, has selective actions compared to T3. In animals, GC1 reduced serum cholesterol and serum triglycerides, probably by stimulation important steps in reverse cholesterol transport. Other selective thyromimetic, KB- 2115 and KB - 141 have similar effects. Another class of thyroid hormone analogs, the thyronamines have emerged recently but the basic biology of this new class of endogenous thyroid hormone remains to better understood. Therefore, these molecules may be a potentially treatment for obesity and reduction cholesterol, triglycerides and lipoprotein (a). To date the studies in human are preliminary. Tolerance and efficacy of these drugs are still under investigation.

[Long-term outcome of the adult onset craniopharyngiomas]. / Devenir à long-terme des craniopharyngiomes de l'adulte.

There is few published series dealing on the long-term outcome of the adult-onset craniopharyngiomas. We report the long term clinical, tomodensitometric and MRI data outcome of 35 (23 woman and 12 men) consecutive adult-onset cured for craniopharyngiomas between 1983 and 2002, and followed-up in Rennes University Hospital. The operation was performed via frontopterional approach in 59% and transphenoïdal approach in 41% of cases. Their age at the time of diagnosis was 44.7+/-15.1 years (21-74). The average postoperation follow-up was 7.4+/-7.0 years (0.1-19.1). Recurrence of tumour occurred in 8 patients (25.8%) and a tumor progression in 1 case. The delay of recurrence after initial surgery was 4.1+/-1.3 years (1.4-6.3). Two patients had 5 and 6 years treatment by growth hormone (GH), without tumor recurrence. The observed increase of weight after the surgical cure of craniopharyngiomas concerned 22 patients (63%). The average weight gain was 17.5+/-14.7 kg (1.5-58). In 7 cases (20%) neuropsychological disorders were noted, of which 2 with lost of professional activity. Three patients died. In conclusion the craniopharyngiomas recurrence is frequent and can appear in very prolonged deadlines after the initial surgery.

[Pilot study and preliminary validation of the French version of a quality-of-life questionnaire specific for subjects with growth hormone deficiency]. / Etude pilote et validation préliminaire de la version française d'un questionnaire de mesure de la qualité de vie spécifique des sujets atteints de déficit en hormone de croissance.

This study forms part of a research project seeking to develop a standardized questionnaire by which clinicians can assess the impact of growth hormone (GH) deficiency and its treatment on the "perceived health" or health-related quality of life of adults. The specific aim of this study was to translate and adapt for French patients the AGHDA (Adult Growth Hormone Deficiency Assessment) a standardized health-related quality of life measure for use with GH-deficient adults, initially developed in the United Kingdom, and to collect data which could be used to assess the main psychometric characteristics of its French version the ISPA-HC (Indicateur de Santé Perceptuelle Adulte-Hormone de Croissance). The main properties analyzed are: 1/ The scale's acceptability, as determined by means of face-to-face interviews with a small number of subjects, then by an ad hoc questionnaire administered during a test-retest study; 2/ The scale's reliability, as determined by a test-retest study (with a 15-days interval between tests); 3/ The scale's concurrent validity, as expressed by comparison with scores obtained by means of a generic quality of life scale, the ISPN (the French version of the Nottingham Health Profile). The results of this first trial with the ISPA-HC are conforming to what one can expect from a good instrument. The ISPA-HC has been shown to have very good levels of reliability and internal consistency. Its scores show a close correlation with those of the ISPN (the French version of the Nottingham Health Profile). This instrument can be used to measure variations in the perceived health of subjects with growth hormone deficiency. Its responsiveness to change is to be examined in subsequent studies.

[Acromegaly due to ectopic GH RH secretion by a bronchial carcinoid tumor: a case report]. / Acromégalie par sécrétion ectopique de GH-RH liée à un carcinoïde bronchique: à propos d'un cas.

Ectopic GH RH is a very uncommon cause of acromegaly (<1% of acromegaly). We report the case of an 41 year-old woman with acromegaly due to a GH-RH-secreting bronchial carcinoid tumor. Elevated serum GH (14 ng/ml) was paradoxically stimulated after glucose loading. Magnetic resonance imaging revealed a normal pituitary gland. The thoracic CT demonstrated a voluminous (8 cm) bronchial tumor visualised with octreotide scintigraphy. Acromegaly due to ectopic GH RH secretion was confirmed by very high plasma immunoreactive GH RH level. After removal of the carcinoid tumor, plasmat GH, IGF1 and GH RH levels were normalised.

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly.

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.

Time course of GH and IGF-1 levels following withdrawal of long-acting octreotide in acromegaly.

AIM: Several studies have demonstrated the efficacy of octreotide LAR administered intramuscularly at 4-week intervals in the treatment of acromegaly. In contrast, few data are available on the time course of GH and IGF-1 plasma levels following octreotide LAR withdrawal. This prompted us to study these parameters for up to 20 weeks following drug withdrawal in a group of 18 acromegalic patients treated for one year. DESIGN AND PATIENTS: We studied 18 patients treated with octreotide LAR 10 mg (n = 2), 20 mg (n = 15) and 30 mg (n = 1) every 4 weeks for one year. GH (mean level during a 4-hour daily profile) and IGF-1 concentrations were measured at the end of treatment, just before the last injection (baseline) and then 15 +/- 2 weeks (first control) after the last injection. In patients with GH levels below 2.5 micrograms/L and/or normal IGF-1 at the first control, a second control was performed four to eight weeks later. RESULTS: After one year of treatment with octreotide LAR, the mean plasma GH concentration was 1.91 +/- 1.25 micrograms/L (mean +/- SE) and the mean IGF-1 concentration was 440 +/- 251 micrograms/L. Among the 18 patients, 13 had mean plasma GH concentrations below 2.5 micrograms/L and seven could be considered as well-controlled (normal IGF1 and mean GH levels below 2.5 micrograms/L). After treatment withdrawal, the plasma GH concentration remained below 2.5 micrograms/L at the first and the second controls in 2 of the 13 (15%) patients with suppressed GH levels on baseline. Among the seven well-controlled patients on baseline (GH levels below 2.5 micrograms/L and normal IGF-1), one (15%) remained well-controlled, one (15%) kept GH levels below 2.5 micrograms/L but increased IGF-1 levels, and one (15%) kept normal IGF-1 levels but increased mean GH levels at the first control. This hormonal status remained unchanged at the second control in these 3 patients. CONCLUSIONS: These results show long-lasting suppression of GH secretion after treatment withdrawal in some acromegalic patients treated for 12 months with octreotide LAR. The duration of GH suppression after treatment withdrawal is variable. Mean GH levels remained below 2.5 micrograms/L in 15% of our patients for up to 21 weeks following withdrawal of octreotide LAR. In practice, it may be preferable to wait several months after long-acting somatostatin analog withdrawal before reassessing hormone status. Owing this long-lasting effect, a dose reduction to 10 mg and/or a longer interval between injections could be considered for very good responders, as this would lead to considerable cost savings without affecting GH or IGF-1 control.

[Anti-TPO antibodies and screening of thyroid dysfunction in type 1 diabetic patients]. / Intérêt du dosage des anticorps anti-TPO pour le dépistage d'une dysthyroïdie chez des patients diabétiques de type 1.

The diagnosis of thyroid dysfunction is often late in type 1 diabetic population. So, the aims of this study were 1) to evaluate the prevalences of thyroperoxydase (TPO) and thyroglobulin (Tg) autoantibodies detected by highly sensitive radioimmunological method in a cohort of 258 adult type 1 diabetic patients without evidence of clinical thyroid disease; 2) to determine whether or not measurement of TPO and/or Tg antibodies can identify subjects at risk of clinical or infraclinical thyroid dysfunction by measuring TSH in the entire group. TPO antibodies were found in 45 of the 258 diabetic patients (17%). The prevalence of TPO antibodies was not influenced by the following factors: gender, duration of disease, age at screening and at diabetes diagnosis, positivity of familial history. Tg antibodies were found in 19 patients (7%), including 13 cases with TPO antibodies. All patients without TPO antibody (n=213), including Tg-positive patients displayed TSH values in normal range. Among the 45 TPO-positive patients, 11 patients displayed infraclinical thyroid dysfunction. At the end of the 5-year follow-up, only 2/45 patients became anti-TPO negative. Thirteen of the 45 patients developed subclinical or clinical thyroid diseases (4 Graves'disease and 9 thyroiditis with hypothyroidism). By contrast, none of 45 TPO negative patients, sex and age matched with the TPO-positive patients, developed during follow-up anti-TPO positivity and/or infraclinical thyroid dysfunction. In conclusion, the determination of TPO antibodies by a highly sensitive method allows identifying diabetic patients with thyroid autoimmunity and at risk of subsequent impaired thyroid function, whatever age at diagnosis and diabetes duration. By contrast, anti-Tg determination did not give further information about subsequent thyroid dysfunction. In TPO antibody positive patients repeated thyroid clinical examination and TSH determination could be recommended to detect infraclinical thyroid dysfunction.

Antithyroid drugs and Graves' disease--prospective randomized assessment of long-term treatment.

OBJECTIVE: Although antithyroid drugs (ATD) are widely used in the treatment of Graves' disease, management protocols, especially treatment duration, remain a subject of debate. The rate of relapse after short-term regimens of less than 6 months with ATD at decreasing doses is higher than after longer treatments from 12 to 24 months. As no prospective study has provided data on even longer protocols exceeding 2 years, we conducted a prospective trial to determine potential benefits of a 42-month treatment compared with an 18-month treatment. DESIGN, PATIENTS AND MEASUREMENTS: The aim of this prospective randomized trial was to compare relapse rates achieved two years after treatment withdrawal in patients who received carbimazole at decreasing doses for 18 months (n = 62) vs 42 months (n = 72). In addition to clinical relapse rate, the percentage of patients who normalized antithyroperoxidase (TPO) antibody and anti-TSH receptor stimulating antibody (TSAb) levels and early iodine uptake at the end of treatment were assessed as outcome criteria. RESULTS: The relapse rate two years after discontinuation of treatment did not differ significantly in patients treated for 18 months from those treated for 42 months (36% vs 29%, NS). At the end of treatment, there was no significant difference between the two groups in the percentage of anti-TPO positive patients (53% vs 46%, NS) or early iodine uptake (27% vs 21%, NS). Although the percentage of patients with TSAb was significantly lower in the 42-month treatment group (18% vs 42%, P = 0.004) at treatment withdrawal, the percentage of TSAb-positive patients did not significantly decrease between 18 and 42 months in this group (27% vs 18%, NS). CONCLUSION: Treatment duration greater than 18 months did not improve remission rate determined 2 years after treatment withdrawal or immunological variables or early iodine uptake measured at the time of discontinuation of treatment. These findings would indicate that, when a defined duration treatment is planned, prolonging treatment beyond 18 months does not provide any additional benefit.

[Synthetic antithyroid drugs and Basedow's disease or the choice of a therapeutic strategy]. / Antithyroïdiens de synthèse et maladie de Basedow ou le choix d'une stratégie thérapeutique.

We present the conclusions of two prospective studies of patients examined at their first manifestation of Graves' disease and treated with antithyroid drugs (ATD). The purpose of the first study was to investigate the effects of long-term treatment: the patients were given carbimazole in degressive doses without hormone replacement for 18 months, the followed up for 2 to 6 years after drug withdrawal. The second study was designed to determine the effect of treatment duration on the prognosis: the patients were given an ATD according to the same protocol for a duration randomly set at either 6 or 18 months, then seen again 2 years after ATD withdrawal. The results showed that after 18 months of treatment at least 50 percent of the patients could be expected to remain in remission for 6 years. Remissions were less frequent when treatment was shorter (41.7 percent after the 6 month treatment versus 61.8 percent after the 18 month treatment, with a 2 years' follow-up; P less than 0.05). The relapses that occurred came early: 70 percent of them took place within the first post-treatment month. This article also provides evidence of high T3 and/or T4 levels without signs of thyrotoxicosis during the post-treatment clinical course; these exclusively biochemical relapses spontaneously disappeared and may have been expressing epidoses of active thyroiditis.(ABSTRACT TRUNCATED AT 250 WORDS)

[Induction of ovulation by pulsatile gonadoliberin administration. Indications and limits]. / Induction de l'ovulation par l'administration pulsatile de gonadolibérine. Indications et limites.

With its simplicity, innocuity and efficacy, pulsatile GnRH administration constitutes a considerable advance in ovulation induction techniques. Its purpose is not to replace classic methods like Clomiphene Citrate, gonadotropins or dopaminergic agonists, but to complement them. While the choice of administration route, IV vs SC is still controversial, the efficacy depends mainly on the selection of the patients susceptible of benefiting from this therapy. Low gonadotropic activity hypothalamic amenorrhea remains the best indication for pulsatile GnRH, as substantiated by the results published over the last 10 years. The other anovulation causes, including PCO-S, are more disputable indications, and prospective studies involving homogeneous populations are necessary to assess the true standing of GnRH in such indications.

Antithyroid drugs and Graves' disease: a prospective randomized evaluation of the efficacy of treatment duration.

A prospective randomized study was performed in patients with hyperthyroid Graves' disease (GD) in order to compare long (18 months) and short term (6 months) antithyroid drug treatment on the remission rate. A therapeutic protocol was offered to all GD patients who had not been treated for this disease previously. All patients studied who followed the protocol were rechecked 2 yr after treatment was withdrawn, or earlier in the case of relapse. Of the patients having undergone long term treatment, 61.8% still were in remission 2 yr after treatment withdrawal, whereas only 41.7% of the patients treated for 6 months were in remission (P less than 0.05). Such findings clearly establish that treatment duration has a direct beneficial incidence on the remission rate. These results were confirmed by the fact that treatment for 18 months resulted in remission in 7 of 15 patients who had previously relapsed after a 6-month course of therapy. This improvement in relation to treatment duration might be due to the immunosuppressive action of carbimazole. No significant difference was observed between relapse and remission groups, regardless of treatment duration, for HLA ABDr, serum T3 and T4, and T3/T4 ratio determined before treatment. Only the thyroid-stimulating antibody levels determined at the time of diagnosis and at the end of treatment were higher in the relapse group, a difference that was relevant only globally, due to value scattering. Furthermore, thyroid-stimulating antibody levels at the end of treatment may indicate remission or, conversely, continuance of the pathological process.(ABSTRACT TRUNCATED AT 250 WORDS)