Pituitary adenomas are a common manifestation of multiple endocrine neoplasia type 1 (MEN1) but most of them occur sporadically. There are only a few well defined genetic abnormalities known to occur in these sporadic tumours. The MEN1 gene located on 11q13 has recently been cloned and allelic deletion and mutation analysis studies have implicated the MEN1 gene in a significant fraction of the sporadic counterparts of typical MEN1 neoplasms (parathyroid tumours, insulinomas and gastrinomas). To determine if MEN1 gene inactivation is also involved in the development of sporadic pituitary adenomas, allelic deletions of chromosome 11q13 and MEN1 gene mutations and polymorphisms were assessed in 35 sporadic tumours of the anterior pituitary (9 prolactin-secreting, 8 GH-secreting, 3 TSH-secreting, 2 TSH/GH-secreting, 4 Cushing, 9 silent). Thirty-one tumours were found to be heterozygous for at least one MEN1 intragenic polymorphism (25 cases) or for a flanking gene polymorphism (6 cases). The remaining tumours were not informative. No mutations were found in any tumour except in one prolactinoma which was homozygous or hemizygous for a mutation (1-117 C-->T) in a region close to the promoter. Unfortunately, blood or normal tissue was not available in this case. Our data show that somatic MEN1 mutations do not contribute significantly to tumorigenesis of sporadic pituitary adenomas and suggest that mutation of other genes are likely to contribute to the pathogenesis of these tumours.
J Poncin, A Stevenaert and A Beckers
J Scibilia, D Finegold, J Dorman, D Becker and A Drash
While the treatment of children with Type I diabetes mellitus has dramatically improved since the introduction of insulin in 1922, significant acute mortality still remains. To better ascertain the causes of death in younger children and adolescents with diabetes mellitus, a retrospective review was undertaken of diabetes associated mortality in the patient population followed at the Children's Hospital of Pittsburgh between the years 1950 and 1985. Fifty-five deaths were identified of which 20 occurred during the initial presentation of diabetes and 35 occurred between 2 months and 11 years following the diagnosis of diabetes mellitus. Diabetic ketoacidosis (DKA) was associated with 64% of the total mortality with 85% of the early onset and 54% of the late onset deaths being ketoacidosis related. Of these ketoacidosis associated deaths, cerebral edema was documented in 31%, or 20% of the total group mortality. Non ketoacidosis deaths in both early and late onset groups were caused by heterogeneous events. There were no deaths associated with the traditional late vascular complications of diabetes mellitus. Since diabetic ketoacidosis is a potentially preventable acute complication of diabetes mellitus and represented a predominant cause of mortality in these children, early recognition and prompt treatment might substantially reduce childhood mortality in patients with Type I diabetes mellitus.
H. Becker, P. Berle, A. Wallé and K. D. Voigt
In 20 normal females various parameters of lipid and carbohydrate metabolism were determined 4 weeks before and 3 and 7 days after delivery. Compared with normal values, in late pregnancy the blood levels of pyruvate, lactate, total lipids, glycerid-glycerol, total glycerol, and free fatty acids were found significantly higher. In puerperium all parameters returned to normal values with the exception of total lipids and free fatty acids which were still elevated at the end of the observation period. Glucose was found in normal range during pregnancy and on the 7th day of puerperium, but on the 3rd day after delivery a significant decrease was observed. The data of this investigation were compared with the results obtained under oral contraceptive treatment. In principal there is a good agreement between the results found during late pregnancy and data obtained under oral contraceptive treatment, the alteration in pregnancy being, however, more marked.
Eladio A. Nunez, William L. Money and David V. Becker
The 'subcellular' localization of radioiodine was observed in the thyroid follicles of rats following the injection (i.p.) of 75 μc to 1000 μc of radioiodide (125I). Twenty-four hours after the injection of the smaller doses (75, 150 and 250 μc), the radioiodine was distributed evenly throughout the follicular lumen. Twenty-four hours after the injection of the large dose (1 mc) of radioiodide, there were two histological patterns of follicular radioiodine localization. In the majority of follicles (about 85%) the radioiodine was distributed uniformly throughout the lumen. In the other follicles (15%) the activity was not uniformly distributed but was primarily localized along the cell-colloid border. At this interface, the radioactivity was entirely localized in the colloidal region.
A possible explanation is that the follicles with an intra-colloidal ring of radioiodine are more sensitive to the early effects of radiation and could be reflecting some cellular biochemical alteration.
W. Bartsch, H. Becker, F.-A. Pinkenburg and M. Krieg
In 128 non-hospitalized men (age range 36–65 years) rectal palpation revealed in 54 cases an enlargement of the prostate (group II), which was very distinct in 20 cases (group III). The measurement of testosterone (T), 5α-dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol (3α-diol) oestradiol (Oe2), sex-hormone-binding-globulin binding capacity (SHBG), luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (Prl) in the blood of normal men (group I) and those with BPH (group II or III) demonstrated no significant differences between the three groups when respective age ranges were compared. A significant increase of FSH and decrease of 3α-diol with age was seen in the normal group (I), which was similar but less pronounced in BPH (groups II and III). A distinct increase of DHT with age was found in BPH (group II), which was not so dominant in normal men (group I). From these data it is concluded that the conversion of DHT to 3α-diol might be reduced in older males independent from the occurrence of BPH and that the hyperplastic prostate possibly secretes significant amounts of DHT into the circulation. These results are discussed with respect to their possible role in the pathogenesis of BPH.
M. Lambert, A. G. Burger, P. De Nayer and C. Beckers
Abstract. In order to test the reactivity of TSH to TRH during amiodarone treatment we investigated 7 hypothyroid subjects treated with 50 μg T3/day. A TRH test (200 μg iv) was performed before and after 6 weeks of treatment with 400 mg amiodarone/day. Amiodarone treatment induced a significant increase in serum total and free T3 (from 2.17 ± 0.13 to 3.55 ± 0.58 nmol/l and from 5.6 ± 0.61 to 9.46 ± 1.41 pmol/l). Basal TSH levels were significantly decreased and the maximal stimulation of TSH 20 min after TRH injection was only 20.0 ± 3.3 mU/l during amiodarone treatment compared with 61.4 ± 10.4 mU/l before treatment. These results indicate that in hypothyroid patients treated with amiodarone, the TSH response to TRH is blunted and that this is likely to be related to the higher total and free T3 levels or to a direct effect of amiodarone at the pituitary level.
HV Socin, P Chanson, B Delemer, A Tabarin, V Rohmer, J Mockel, A Stevenaert and A Beckers
OBJECTIVE: Our aim was to report the recent changes in diagnosis and management of TSH-secreting pituitary adenomas. METHODS: We retrieved 43 consecutive patients with TSH-secreting pituitary tumors (23 male and 20 female) among 4400 pituitary adenomas followed between 1976 and 2001 in six Belgian and French centers. RESULTS: TSH was elevated in 18/43 and alpha subunit in 13/32 patients. In patients with intact thyroid (n=30), mean free tri-iodothyronine was 13.1 pmol/l (range 3.5-23) and mean free thyroxine was 38.4 pmol/l (range 10.2-62.7). Hyperprolactinemia and acromegaly were associated in 9/43 and 8/43 cases. The number of associated hypersecretions was higher in macroadenomas than in microadenomas (Chi square = 11.2, P<0.01). Two women had sporadic multiple endocrine neoplasia type 1-associated syndrome. The proportion of microadenomas versus macroadenomas was 1/11 (period 1974-1986) and 8/32 (period 1987-2001). Bilateral petrosal sinus sampling, (111)In-pentreotide scintigraphy and ((11)C)-l-methionine positron emission tomography scan confirmed diagnosis in four questionable microadenomas. Macroadenomas with extrasellar extension (31 cases) had a tendency to be medially located. Medical treatment with somatostatin analogs was initiated as first-line treatment in 26 patients. TSH levels were reduced by more than 50% in 23/26 cases. A tumoral shrinkage of more than 20% was observed in 5/13 cases. Surgery was performed in 36 patients. After 1 year, 21 of them (58.3%) met the criteria of surgical favorable outcome. Pituitary radiotherapy (n=8) and somatostatin analogs allowed normalization in cases not cured by surgery. CONCLUSION: Ultrasensitive methods for TSH measurement led to an earlier recognition of TSH-secreting pituitary tumors. In this series, we observed that TSH-secreting pituitary tumors are today more frequently found at the stage of microadenomas, medially located, without associated hypersecretions and needing new exploration methods as compared with older series. This changing spectrum in the presentation of TSH-secreting pituitary tumors and the excellent response to somatostatin analogs has been accompanied by an improvement in the prognosis of the disease.
C. Beckers, J. Barzelatto, C. Stevenson, A. Gianetti, A. Pardo, E. Bobadilla and M. De Visscher
Iodine kinetic studies have been performed in 61 Indians from the Pedregoso goitre endemic in Chile. The daily absolute iodine uptake in the thyroid averaged 98 μg I, with maximal values in the cases of diffuse goitre. The mean thyroxine degradation rate in the same group of patients corresponded to 102 μg I per day, when using the mean thyroxine distribution space and thyroxine (T4) fractional turnover rate obtained from a comparable group of the same population. The output of iodine from the thyroid was calculated by 3 different methods. In each case, the iodine output appears to be higher than the amount of halogen accumulated by the thyroid or metabolized by the tissues.
These findings suggest an important spillage of iodine (as iodide and/or iodinated tyrosines) by the goitrous gland. Such a disturbance apart from nutritional iodine deficiency may be an important factor in the pathogenesis of endemic goiter.
A. Beckers, R. Courtoy, A. Stevenaert, J. Boniver, J. Closset, F. Frankenne, M. Reznik and G. Hennen
Abstract. Hormone production was studied in situ by immunocytochemical methods in 20 pituitary adenomas. Special attention was given to 13 adenomas removed from acromegalic patients. Out of them, 6 had mild to moderate hyperprolactinemia. Immunohistochemistry revealed PRL-containing cells without any close relationship with high PRL serum level in 6 patients. Double immunogold staining revealed mammosomatotrope cells characterized by simultaneous presence of GH and PRL in the same granules in 2 patients. Since mammosomatotropes have never been demonstrated in the normal pituitary, our results probably signify gene dysregulation in pituitary cells of those acromegalic patients.
P Petrossians, N Ronci, H Valdes Socin, A Kalife, A Stevenaert, B Bloch, A Tabarin and A Beckers
OBJECTIVES: The authors present a case report that proposes the use of cabergoline treatment in silent ACTH adenoma, an unusual member of the heterogeneous group of the so-called clinically non-functioning pituitary adenomas. DESIGN: Following the clinical and radiological improvement of a recurrent silent ACTH adenoma in a 77-year-old patient treated with cabergoline (0.5 mg every 2 days for 2 years), in vitro studies of the original tumor were performed. METHODS: The original tumor from the patient was studied by in situ hybridization and dopamine D2 receptor autoradiography. It was compared with four macroprolactinomas and two macroadenomas from patients with Cushing's disease. RESULTS: The D2 receptor mRNA signal of the reported case was intense and of the same order of magnitude as that observed in control prolactinomas. Dopamine D2 receptor autoradiography was twice that of control corticotroph adenomas and was close to that observed in prolactinomas. CONCLUSIONS: This is the first description of an in vivo shrinkage of an ACTH silent adenoma under cabergoline. We demonstrate in vitro, the presence of D2 receptors in the primitive tumor in concentrations similar to those found in control prolactinomas. These results suggest that therapeutic trials with cabergoline might be undertaken in recurring cases of ACTH silent tumors and more generally, non-functioning pituitary adenomas.