[Importance of searching for hypogonadism in patients with a longstanding history of leg ulcers?]. / Quel est l'intérêt de rechercher un hypogonadisme chez un patient présentant des ulcères de jambe récidivant depuis l'âge de 20 ans?

Androgen replacement therapy has been reported to have a beneficial effect in patients with Klinefelter's syndrome or perforating plantar ulcers. We report the case of a 55-year-old man with a 35-year history of leg ulcers and venous insufficiency. His leg ulcers healed 4 months after a management scheme including vascular rehabilitation (intermittent pressure therapy, ankle mobilization, multiple layer compression bands on the lower limbs), skin grafts and foam sclerotherapy of the great saphenous vein. The ulcers recurred 1 month later. This recurrence and the unusually young age for development of venous leg ulcers led to a search for a rare cause. The diagnosis of anterior pituitary failure was established. Sclerotherapy and androgen replacement therapy led to complete healing without recurrence at the 1-year follow-up visit. A link between androgen deficiency and fibrinolysis, protein synthesis deficiency, inflammation and trophicity is well documented in the literature. A search for hypogonadism may be useful in young patients presenting a longstanding history of leg ulcers or in patients with suspected andropause irrespective of age.

[Self-monitoring of blood glucose in type 2 diabetic patients. What could we propose according to their treatment?]. / Autosurveillance glycémique pour le patient diabétique de type 2: qu'en attendre selon le schéma thérapeutique?

Self-monitoring of blood glucose (SMBG) is well acknowledged in type 1 diabetes mellitus (DM). However, although its use is widely recommended in some developed countries, with a significant economical cost, SMBG remains questionable in type 2 DM because its efficacy is not demonstrated by high-quality randomized controlled trials. Type 2 diabetes is an heterogenous disease and its natural history covers several decades. Although type 2 DM represents an important risk of microvascular and cardiovascular complications, it remains asymptomatic for a long time with often a very poor metabolic control and low drug compliance. Treatment of type 2 diabetes varies during these decades, changes in lifestyle at the very beginning, then using oral drugs without risk to develop hypoglycemia (metformin, glitazones, alpha-glucosidases inhibitors) and/or insulin secreting drugs (sulfonylureas or glinides) with potential hypoglycemic risks. At every stage, SMBG could sensitize the patient and possibly could improve glycemias and compliance. SMBG must be adapted to provide informations representing a very useful, motivating and pedagogic tool. Obviously SMBG, in non-insulin-treated type 2 DM, targets other objectives when compared to its use in type 1 DM requiring adapted educational programs to avoid its uselessness and depression of the patient. In insulin treated type 2 DM patients, with a bed time regimen, SMBG represents both a major tool for adjusting the insulin and oral hypoglycemic drugs doses and a comprehensive instrument for controlling and understanding the disease. Thus SMBG is a logical tool for the management of a large proportion of type 2 DM patients but it requires to be proposed in structured counseling educational programs adapted to the psychological and social profile of the patients. These programs must be evaluated by randomized controlled trials.

[Prolonged suppressive L-thyroxine therapy. Longitudinal study of the effect of LT4 on bone mineral density and bone metabolism markers in 71 patients]. / Traitement prolongé par L-thyroxine à visée suppressive. Etude longitudinale de l'influence de la LT4 sur la densité minérale osseuse et les marqueurs osseux métaboliques chez 71 patients.

OBJECTIVES: A prospective longitudinal study was conducted to investigate the influence of prolonged suppressive L-thyroxin therapy on bone density and biochemical markers of bone remodeling. PATIENTS AND METHODS: Seventy-one patients (including 28 menopaused women) taking long-term L-T4 for thyroid carcinoma were divided into 3 groups according to their TSH level: low (TSH < 0.04 mlU/l), moderate (0.04 TSH < or = 0.10 mlU/l) and high (TSH > 0.10 mlU/l). Bone density was measured in lumbar vertebrae annually for a mean 4.5 years. Bone metabolism markers were measured over a 4 year period. Bone density measurements of the femur were also obtained for 2 years in 16 menopaused women. RESULTS: Lumbar bone density did not decline whatever the TSH level or the duration of L-T4 treatment. Likewise for menopaused women without substitution estroprogesterone therapy. Over the 4 years, biochemical markers of bone formation, including bone alkaline phosphatases and osteocalcin, or of bone resorption, including urinary hydroxyprolin, did not vary. In addition, in menopaused women, femoral bone density was not significantly lowered over the 2 years follow-up. No lumbar or femoral osteopenia was observed in these patients taking L-thyroxin, even for those with complete TSH blockade. Biochemical markers did not demonstrate a significant acceleration of bone turnover during prolonged administration of L-T4 at suppressive levels.

Cytotoxic therapy with etoposide and cisplatin in advanced adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare tumour with a poor prognosis. Cisplatin is the most widely tested cytotoxic agent in this disease. A total of 18 patients with advanced ACC were enrolled. Cytotoxic therapy consisted of etoposide (VP16) (100 mg m(-2) day(-1) on days 1-3) and cisplatin (100 mg m(-2) day(-1) on day 1) every 4 weeks. Mitotane treatment was maintained during chemotherapy in 14 patients. A complete response was observed in three cases and a partial response in three cases, giving an overall response rate of 33%. Tumour response was observed in three of the six patients with progressive disease during treatment with mitotane given at an effective dosage, as shown by serum levels >14 mg l(-1). Toxic effects were as expected and were non-life-threatening; no treatment interruption was required.

Pentagastrin testing in patients with renal insufficiency: normal responsivity of mature calcitonin.

Calcitonin (CT) is the most sensitive tumor marker for medullary thyroid carcinoma available, but it lacks specificity. Chronic renal failure (CRF) is known to be associated with elevations of serum immunoreactive calcitonin. Using an immunoradiometric assay to detect only mature CT, we evaluated the basal CT level and its response to pentagastrin in 30 patients with CRF and compared these data with those obtained in 71 controls. Basal mature CT was significantly higher (p < 0.05) in patients with CRF (3.55 pg/mL) than in controls (2.00). Among these patients, 20% had basal CT levels more than 10 pg/mL with a maximum of 51 pg/mL. Peak CT values (highest value obtained 3 or 5 minutes after pentagastrin) were comparable in the two groups. Among patients with CRF, 10% had peak CT values greater than 30 pg/mL with a maximum of 53 pg/mL. In this group of patients, no correlation was found between CT (at any time during the test) and parathyroid hormone, calcium, phosphate, or creatinine clearance. Men had significantly higher CT values compared with women at each time point tested, including peak values. Patients with CRF, who have not yet undergone dialysis, have moderately elevated basal CT levels, but have normal pentagastrin-stimulated peak CT levels.

[Isolated thyroid nodule. Comparative value of cyto-puncture and scintigraphy]. / Nodule thyroïdien isolé. Intérêt comparé de la cytoponction et de la scintigraphie.

OBJECTIVES: Nodular thyroid disease, indicated by the presence of single or multiple nodules within the thyroid gland is a common clinical problem, the main question remains the malignancy. Radionuclide scanning, ultrasonography and fine needle aspiration biopsy have been helpful to distinguish benign from malignant nodules and to select patients for surgery. METHODS: We performed a prospective study to assess the comparative value of fine needle nonaspiration biopsy and thyroid scinti scan in the management of 412 patients operated for solitary thyroid nodule. RESULTS: Sensitivity and negative predictive values were the same for both methods, but specificity of cytology was greater than that of thyroid scinti scan (80.53% vs. 10.47%, p < 0.001). DISCUSSION: Thyroid radionuclide scanning remains valuable in the evaluation of a cytological benign solitary thyroid nodule when TSH value is low, in order to distinguish toxic adenoma from cold nodule in Graves' disease.

Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group.

The aim of our study was to assess the ability of routine calcitonin (CT) measurement to improve the preoperative diagnosis of medullary thyroid carcinoma (MTC) in nodular thyroid diseases. We systematically determined basal CT in 1167 patients before thyroid surgery and performed a pentagastrin (Pg) CT stimulation test in 121 of these patients whose basal CT level was normal. Sixteen MTC (1.37%) were found on histopathological examination of surgical specimens: 14 in the 34 patients (41.1%) with abnormal basal CT levels and 2 in the 1133 patients with normal basal CT levels (0.17%). An abnormal increase in Pg-stimulated CT was observed in 7 of the 121 patients tested and was related to microscopic MTC in 2 cases. Among 1167 thyroidectomized patients with nodular thyroid diseases, the prevalence of MTC was 1.37% and reached 41.1% when the basal CT level was abnormal (3% of the patients). CT evaluation detected MTC, whereas other procedures, such as fine needle aspiration cytology, failed, thus allowing early radical surgery. CT measurement should thus become a routine part of the diagnostic evaluation of nodular thyroid diseases.

Multiple endocrine neoplasia type 2: management of patients and subjects at risk. French Study Group on Calcitonin-Secreting Tumors (GETC).

Multiple endocrine neoplasia type 2 (MEN-2) is an inherited multiglandular disease with age-related penetrance and variable expression. The prognosis of MEN-2 is linked to the carcinological evolution of medullary thyroid cancer (MTC), which depends mainly on the stage of discovery, and to the incidents related to pheochromocytomas. The emphasizes the need for early diagnosis and management of MEN-2. Since 1993, mutations evidenced on the protooncogene RET have allowed subjects at risk to be identified, thus leading to a three-step management of these patients. (1) For all the potentially affected members of a MEN-2 family, screening by molecular genetics of the ret gene enables one to identify the subjects at risk who bear the mutation. When no mutation is observed, a linkage analysis study may be proposed. (2) In the subjects at risk, early screening for the various types of endocrine lesions may then start in childhood and be performed using specific biological markers of MTC, pheochromocytoma and primary hyperparathyroidism, and particularly, basal and pentagastrin-stimulated calcitonin measurement, which is known to be the most sensitive marker for the monitoring of MTC. (3) This step of biological investigations enables the earliest possible treatment of any endocrine lesion detected before it is expressed clinically, thus improving the prognosis of MEN-2. When genetic screening cannot be performed, only annual clinical and biological monitoring remain available in all members of a family affected with MEN-2.

Results of the calcitonin stimulation test in normal volunteers compared with genetically unaffected members of MEN 2A and familial medullary thyroid carcinoma families.

In the multiple endocrine neoplasia (MEN) type 2A and in the familial medullary thyroid carcinoma (FMTC), the recent development of genetic testing has provided new methods of identifying disease gene carriers. The use of sensitive immunoradiometric calcitonin (CT) assays led us to evaluate reference ranges of plasma CT responses after pentagastrin in healthy subjects in order to discuss the place of pentagastrin testing in the management of hereditary MTC. Basal and pentagastrin-stimulated CT concentrations were measured in 71 healthy volunteers--aged 20-67 years--and 76 genetically unaffected members of families with hereditary MTC--aged 4-61 years. In healthy subjects, CT peak values were below 30 ng/l in 68 cases and below 50 ng/l in 3 cases. In the genetically unaffected patients, CT peak values were below 15 ng/l in young patients and below 30 ng/l in patients older than 19 year excepted 5 men with stimulated CT levels ranging from 36.5 to 52 ng/l. In 2 of these 5, thyroidectomy revealed C-cell hyperplasia. Borderline test results are not sufficient to establish diagnosis of MTC and in these familial syndromes, management has to be based on the results of genetic testing. However, the determination of the upper normal limit for stimulated CT concentrations in young patients (< 15 ng/l) may help to identify the optimal moment for surgery.

Spontaneous multiple vertebral fractures revealed primary haemochromatosis.

The association of haemochromatosis and bone disease is well established, but osteoporotic fracture is an unusual presentation of the disease. We describe a male patient with osteoporotic fractures as a presenting feature of haemochromatosis. The bone histomorphometry showed a dramatic decrease in trabecular bone volume associated with a decrease in cortical bone thickness. Osteoblastic and osteoclastic activities were reduced without any sign of osteomalacia. Staining for iron with Perl's stain showed focal localization at the interface between mineralized trabecular bone and bone marrow. This observation leads us to review the possible mechanisms of osteoporosis.

[Hypercalcitoninemia in conditions other than medullary cancers of the thyroid]. / Les hypercalcitoninémies en dehors des cancers médullaires de la thyroïde.

Serum calcitonin (CT) assays are the most useful tumoral marker for the diagnosis and follow up of medullary thyroid carcinoma (MTC). Since 1988 the sensitivity and specificity of CT assays have been considerably improved. Normal basal and pentagastrin (Pg) stimulated CT ranges remain to be established and it appears necessary to determine the pathological circumstances which may be responsible for hypercalcitoninemia in addition to MCT. By reviewing literature and data from the "Groupe d'Etude des Tumeurs à Calcitonine": a/we compared basal and Pg stimulated CT values obtained with two commercially available immunometric CT assays and we observed that CT values measured by the CT-EASIA MEDGE-NIX kit were three fold the values obtained by suing the hGH ELSA CIS BIOINDUSTRIE Kit; b/we determined that hypercalcitoninemia may be observed in isolated C Cell Hyperplasia (HCC) surrounding either lymphocytic thyroiditis or follicular thyroid carcinoma loci, in chronic renal failure on maintenance hemodialysis, and in various neuroendocrine tumors. Surprisingly, the hypercalcitoninemia related to HCC has been found in genetically unaffected members (without any identified gene RET mutation) of both a Multiple Endocrine Neoplasia type 2A and isolated familial hereditary MTC.

Comparison of the analytical and clinical performances of three thyrotropin immunoassay kits.

We first compared the analytical performances in terms of precision of two different generation thyrotropin (TSH) assays: Amerlite TSH-60 Assay (K2-TSH) versus Berilux hTSH (B3-TSH) and Kodak Amerlite TSH-30 Ultrasensitive Assay (K3-TSH). Then, we compared the clinical performances in 69 thyrotropin-suppressed patients with thyroid cancer and in 17 other patients referred for newly diagnosed hyperthyroidism. All the patients were given 200 micrograms of Protirelin IV for TRH testing. At the analytical level, the functional detection limit (FDL) was 0.006, 0.017, and 0.04 mU/l for B3-, K3-, and K2-TSH, respectively. At the clinical level of the 17 hyperthyroid patients, 52.9% displayed a positive TRH test with B3, 5.9% with K3, and 11.8% with K2; besides, 29.4% had a basal TSH detectable value with B3, 5.9% with K3, and 11.8% with K2. Among the patients receiving suppressive therapy: 1) 95.6%, 49.3%, and 50.7% showed a detectable TSH response to TRH, with B3-TSH, K2-TSH, and K3-TSH, respectively, and 2) only 5.8% had undetectable basal TSH values with Berilux hTSH, versus 84% with K2 and 89.8% with K3. Considering our findings, we first conclude that third generation TSH assays (having a functional sensitivity limit between 0.01 and 0.02 mU/l) can be useful for monitoring patients on thyroxine suppressive therapy, so as to distinguish partial from more complete thyrotropin suppression. Secondly, even though K3 has a FDL consistent with a third generation TSH assay, it appears less clinically sensitive than B3. Yet, no current assay can thoroughly ascertain a state of overtreatment. Finally, it is important to routinely determine the FDL, which can vary from one kit to the other, within one generation of TSH assays. Indeed, B3 with a FDL at 0.006 mU/l is more useful for monitoring LT4-suppressed patients for thyroid cancer than K3 whose FDL is 0.017 mU/l.

[Hyperthyroidism induced by amiodarone and hyperthyroidism induced by iodine. Histologic, immunohistochemical and ultrastructural aspects]. / Hyperthyroïdies induites par l'amiodarone et hyperthyroïdies induites par l'iode. Aspects histologiques, immunohistochimiques et ultrastructuraux.

Amiodarone is a widely-used anti-arythmic drug that induces an iodine overload and, in 1 to 23% of the patients, a thyrotoxicosis. In a few cases, the thyrotoxicosis may be refractory to conventional pharmacological therapy, thus leading to thyroidectomy. We report the thyroid gland pathology in 5 thyroidectomies that were performed for uncontrolled thyrotoxicosis, induced by amiodarone (4 cases) and by Colchimax, another iodine-rich drug (1 case). Two cases have been studied by electron microscopy. Pathologic findings were: [1] colloid transformation of the parenchyma, [2] areas of follicular disruption with numerous foamy macrophages in the colloid, [3] regenerative areas and [4] a moderate T lymphocytic infiltration. No lysosomal lamellar inclusion body was found by electron microscopy. These lesions may be rather specific of an iodine toxicity. The pathogeny is still misunderstood, and probably complex. It may essentially involve toxic mechanisms, as well as immunologic or allergic mechanisms.

C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective quantitative study of 112 cases.

Since the first description by Wolfe et al of C-cell hyperplasia (CCH) in asymptomatic relatives of patients suffering from a medullary thyroid carcinoma (MTC), several investigators have described CCH associated with a chronic lymphocytic thyroiditis (CLT) not within the context of MTC or multiple endocrine neoplasia (MEN). We report the study of C-cell density in 112 cases of CLT on retrospective surgical material to determine the frequency of the association between CCH and CLT. The cases of CLT were compared with 19 normal thyroid glands obtained at necropsy. C cells, immunoreactive with a polyclonal anti-calcitonin (CT) antibody, were counted at high magnification (X400) and the number of low-power magnification (X100) microscopic fields (LPFs) containing at least 50 C cells per slide was assessed. Image analysis was performed to determine the C-cell density expressed in number of C cells/cm2. C-cell hyperplasia was defined by the following criteria: C-cell density > 40 cells/cm2 and the presence of at least three LPFs containing more than 50 C cells. Twenty percent of the cases of CLT showed a CCH thus defined, and four of them had an elevated serum CT level. Statistical analysis showed no clinical or biological correlation with the presence of CCH. However, the frequency of CCH was higher if a follicular cell carcinoma was associated with CLT. This study confirms a pathological association between CCH and CLT, provides new criteria for the definition of CCH on surgical pathology material, and reports four cases with an elevated serum CT level not within the context of MTC or MEN.

Induction of glioma cell death by 1,25(OH)2 vitamin D3: towards an endocrine therapy of brain tumors?

The secosteroid 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3) is the major biologically active metabolite of vitamin D. Antitumor activity of this hormone has been observed on several cell lines and on breast cancer in vivo. The purpose of this in vitro study was to determine the possible effect of 1,25(OH)2D3 on glioma cells. Two glioma cell lines from rat (C6) or human (GHD) origin were cultured in the presence of 1,25(OH)2D3. The sensitivity of these cells to 1,25 (OH)2D3 was assessed with a colorimetric MTT assay. A cytotoxic effect of 1,25(OH)2D3 was detected at concentrations around 10(-8) M. A lag period of 3 days was required between the onset of the treatment and the observation of the effects. However, the continuous presence of 1,25(OH)2D3 is not required since cell death occurred even when C6 cells were challenged for 24 hr with 1,25(OH)2D3 and then cultured in the absence of the hormone. In addition, 1,25(OH)2D3 regulates the expression of its own receptors in C6 glioma. These results provide to our knowledge the first evidence for a cytotoxic effect of 1,25(OH)2D3 on rat and human glioma cells and could offer both an experimental model to study a programmed cell death in a brain-derived cell line and a new strategy for the inhibition of glioma growth in vivo.