AME position statement on adrenal incidentaloma.

OBJECTIVE: To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN: A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT: Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Malignant struma ovarii: a case report and review of the literature.

Malignant struma ovarii is a very rare disease. Only few cases are reported in literature. Because of its rarity, there are various approaches to its treatment. We describe a case of malignant struma ovarii, in a 37 year-old female who presented for non cyclic, chronic pelvic pain and the presence of a right ovarian cyst with mean diameter of 7 cm. The patient was treated with laparoscopic right ovariectomy and with multiple biopsies of omental, left ovary and utero-sacral ligament. The patient underwent subsequently total thyroidectomy and radioiodine (131I) ablation. A Medline literature search was performed; we found 48 cases of malignant struma ovarii. The therapeutic management of the disease is very different in the described case; particularly after surgical removing of the ovarian mass, the treatment is still controversial. We think that the management of malignant struma ovarii could be the same than carcinoma of the thyroid, so after surgical removing of ovarian neoplasm, we recommend thyroidectomy, radiotherapy with 131I and levothyroxine suppressive therapy.

Allelic loss in parathyroid tumors from individuals homozygous for multiple endocrine neoplasia type 1.

Homozygosity for the multiple endocrine neoplasia type 1 (MEN1) gene mutation was described in two of three affected siblings of a kindred in which both parents and the third daughter were heterozygotes. Surprisingly, in the two homozygotes, the disease history did not differ from the one of the heterozygotes. In the attempt to unravel genetic differences in parathyroid tumorigenesis between homozygotes and heterozygotes, restriction fragment length polymorphism analysis and microsatellite PCR analysis for loss of heterozygosity (LOH) at the MEN1 gene region on chromosome 11q13 was performed in parathyroid tissues removed at surgery from the mother, her heterozygous sister, and the three siblings. Allelic losses were evidenced in the larger glands of each patient, with a similar pattern of chromosome 11q12-13 losses. The somatic mutation consisted of a large lose of genetic material from chromosome 11. No gross differences exist in the 11q12-13 LOH observed between homozygous and heterozygous carriers. Interestingly, one of the parathyroid tumors from one heterozygote exhibited region of skipped LOH at the 11q12-13 region. The region in the depth of the critical interval retained heterozygosity, whereas those flanking it shared LOH. These findings indicate that inactivation of both copies of the MEN1 gene are not sufficient for parathyroid tumor development in MEN 1 patients and that tumor suppressor genes, other than the MEN1 gene on chromosome 11 or on other chromosomes, can be involved in the pathogenesis of parathyroid tumorigenesis in MEN 1 syndrome.

The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women.

To assess whether androgen excess per se might impair insulin action, insulin sensitivity was measured by a two-step (20 and 80 mU/m2.min) hyperinsulinemic euglycemic clamp combined with indirect calorimetry and tracer glucose infusion in 43 women (13 obese and 30 nonobese) with normal glucose tolerance and clinical evidence of increased androgen action (hirsutism and/or polycystic ovary syndrome) as well as 12 age- and body mass index-matched healthy controls. Hyperandrogenic women were studied basally and after 3-4 months of antiandrogen treatment with 3 different drugs: spironolactone (n = 23), flutamide (n = 10), or the GnRH agonist buserelin (n = 10). Six women given spironolactone were also reexamined after 1 yr of therapy. At baseline, insulin-mediated glucose uptake was lower in hyperandrogenic women than in controls (by ANOVA, F = 14.3; P < 0.001). Insulin resistance was observed in both ovarian and nonovarian hyperandrogenism, as distinguished by acute GnRH agonist testing. After antiandrogen therapy, insulin action on glucose metabolism significantly increased for both the patients as a whole (F = 7.4; P < 0.01) and each treatment group separately. However, insulin action remained lower than in controls and showed no further improvement in patients reevaluated after I yr of treatment. Increases in both oxidative and nonoxidative glucose metabolism accounted for the improvement in substrate disposal induced by antiandrogen drugs. The increase in the effectiveness of insulin was greater in the lean subjects, whereas the change was small and not statistically significant in the obese women. Response to treatment was more pronounced in women with nonovarian hyperandrogenism, particularly at the low insulin infusion rate. Endogenous glucose production in hyperandrogenic patients was similar to that in healthy women and was unaffected by therapy. In conclusion, antiandrogen treatment partially reversed the peripheral insulin resistance associated with hyperandrogenism regardless of which antiandrogen was used. These data strongly suggest that in women, androgen excess per se contributes to impairment of insulin action.

Genetic screening to identify the gene carrier in Italian and German kindreds affected by multiple endocrine neoplasia type 1 (MEN 1) syndrome.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominantly inherited disorder characterized by parathyroid hyperplasia, anterior pituitary adenomas and neoplasms of the endocrine cells of the gastroenteric tract. It has been established that also other tissues exhibit excessive proliferation associated to the MEN 1 syndrome: carcinoids (bronchial and intestinal), lipomas (visceral and cutaneous), thyroid adenomas and goiter, and adrenal gland cortex adenomas. The men 1 gene has been mapped by genetic studies to the long arm of human chromosome 11, region q12-13. Genetic analysis of families and tumoral deletion mapping made possible to narrow the men 1 region to a 5 cM interval on chromosome 11q12-13. Thirteen marker complexes (17 DNA probes) were found to be linked to the men 1 gene and they span a 14% meiotic recombination with the men 1 locus in the middle. We report a genetic study on 103 subjects from 7 collected MEN 1-kindreds, six Italian and one German, including 30 affected individuals. By linkage analysis to 9 DNA markers (10 DNA probes) of the chromosome region where the men 1 gene maps (11q12-13), we identified 10 mutant gene carriers. The predicted MEN 1 diagnosis was clinically confirmed for 2 of these identified carriers. A predictive accuracy of this genetic test can reach up to 99.5% when it is possible to exclude meiotic crossing-over between the analyzed DNA markers and the disease locus.

Homozygotes for the autosomal dominant neoplasia syndrome (MEN1).

Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, we had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the three siblings and their parents and relatives were genotyped for 12 markers tightly linked to the MEN1 locus, at 11q13, two of the siblings were found to be homozygotes, and one a heterozygote, for MEN1. With regard to the MEN1 syndrome, no phenotypic differences were observed between the two homozygotes and the heterozygotes. However, the two homozygotes showed unexplained infertility, which was not the case for any of the heterozygotes. Thus, MEN1 appears to be a disease with complete dominance, and the presence of two MEN1 alleles with mutations of the type that occur constitutionally may be insufficient for tumor development.