Carmela Asteria

Thyrotropin-secreting pituitary adenomas

Normal or elevated thyrotropin (TSH) levels in hyperthyroid patients are characteristic of rare TSH-secreting pituitary adenoma (TSH-oma), which is easily detectable by computed tomographic (CT) scan or magnetic resonance imaging (MRI). Other diagnostic aids are an absent/impaired TSH response to thyrotropin-releasing hormone (TRH), discrepant TSH and alpha-subunit responses to TRH, high sex hormone-binding globulin (SHBG) levels, high alpha-subunit levels, and a high alpha-subunit/TSH molar ratio. Familial studies help rule out thyroid hormone resistance (RTH). Surgical removal of TSH-oma leads to clinical and biochemical remission in most patients. In surgical failures, radiotherapy and octreotide treatment have a high success rate. Undetectable TSH 1 week postsurgery suggests a definitive cure, backed up by tests for cosecreted hormones from the adenoma and dynamic tests of TSH suppression.

Resistance to Thyroid Hormone

The concept of a hormone-resistant disease has been introduced around the 1940s by Fuller Albright by studying the rickets resistant to Vitamin D therapy and the “Pseudohypoparathyroidism—an example of Seabright-Bantam syndrome” (1,2).He called the disease “pseudo,” as the patients showed clinical features of hypoparathyroidism, but the injection of parathyroid hormone was not followed by the expected increases of serum calcium levels and urinary phosphate excretion. Thus, the term “pseudo” entered into the medical vocabulary to indicate an endocrine disorder resembling a known disease, but accompanied by failure of the end-organ to respond to the specific hormone. Several examples of insensitivity to many hormones, including insulin, corticosteroids, androgens, estrogens, anterior and posterior pituitary hormones, have been reported in the last 50 yr. Moreover, it is now clearly demonstrated that genetic mutations of hormone receptor proteins or proteins involved in the signal transduction are the underlying cause of most clinical conditions that we prefer today to call not “pseudo,” but “resistance to thyroid hormone action.”

Pituitary Resistance to Thyroid Hormones

Pituitary thyroid hormone resistance (PRTH) refers to a particular form of thyroid hormone refractoriness that is accompanied by peripheral hyperthyroidism, as only the TSH-secreting pituitary cells appear to be resistant to the effects of thyroid hormones. The presence of PRTH is suspected and diagnosed on the basis of the finding of high free thyroid hormone levels along with unsuppressed TSH, clinical signs and symptoms of hyperthyroidism and values of at least one of the parameters evaluating peripheral thyroid hormone action in the hyperthyroid range. However, most patients with PRTH present with clinical signs and symptoms of thyroid dysfunction, particularly goiter and tachycardia, overlapping those recorded in patients with generalized thyroid hormone resistance (GRTH), i.e. refractoriness to thyroid hormones at both pituitary and peripheral tissue level. Moreover, most of them display normal values of other parameters evaluating the peripheral effects of thyroid hormones and bear mutations in the gene encoding for T3 nuclear receptors similar to those found in patients with GRTH. These findings are questioning the existence of PRTH as a separate clinical entity and support the view that the various forms of thyroid hormone resistance may be part of a spectrum of disease with variable expression in different issues.

Loss of heterozygosity of the MEN1 gene in a large series of TSH-secreting pituitary adenomas

Thyrotropin-secreting pituitary adenomas (TSH-omas) are rare tumors (0.5% of all pituitary adenomas) showing an invasive behavior and usually sporadic, although a few cases are associated with multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant inherited syndrome. This disorder is linked to loss of heterozygosity (LOH) on 11q13 and inactivating mutations of MEN1 gene, which is located in the same chromosomal region. As other types of anterior pituitary adenomas, TSH-omas are the result of a monoclonal outgrowth where the intrinsic genetic defects involving oncogenes or tumor suppressor genes occur in a progenitor cell. However, so far no activating mutations of particular oncogenes or inactivating mutations of tumor suppressor genes have been identified. Starting from the observation that 3–30% of sporadic pituitary adenomas show LOH on 11q13, and that allelic losses on the long arms of chromosome 11, beside 10 and 13, are significantly associated with the transition from the non-invasive to the invasive phenotype, we decided to investigate LOH on 11q13 and mutations of menin in a large series of TSH-omas. Thirteen tumors were evaluated. DNA was extracted from tumors by standard methods and genomic DNA from peripheral blood leukocytes was used as control. LOH was screened by using 3 polymorphic markers on 11q13: D11S956, PYGM, INT-2. In 3 out of 15 cases we could demonstrate LOH on 11q13, but none of the tumors showed menin mutation after sequence analysis. These data strongly suggest that menin does not play a causative role in the development of TSH-omas, and are in agreement with other studies demonstrating a limited role of menin in pituitary sporadic tumorigenesis.

MEN1 gene mutations are a rare event in patients with sporadic neuroendocrine tumors

BACKGROUND: Neuroendocrine tumors of the gastroenteropancreatic (GEP) tract are encountered either as a sporadic type or as part of multiple endocrine neoplasia type 1 (MEN-1) syndrome. Inactivating MEN1 gene mutations have been found to be responsible for this syndrome and have also been described in sporadic cases. The aim of the present study was to evaluate the presence of mutations in the MEN1 gene in a series of 10 well-differentiated neuroendocrine tumors: five of the foregut and five of the midgut tract. METHODS: Retrospective screening for MEN1 gene mutations was carried out in 10 archived, paraffin-embedded neuroendocrine tumors. Polymerase chain reaction amplification and automated sequence analysis of the DNA extracted from the tumors were performed. RESULTS: One mutation (359 del 4) in exon 2 of the MEN1 gene was identified in a neuroendocrine tumor of the foregut (VIPoma of the pancreas). No mutation was identified in midgut neuroendocrine tumors. CONCLUSIONS: Our data confirm that retrospective genetic analysis can be used to identify mutations in the MEN1 gene and indicate that somatic MEN1 gene mutations are a rare event in sporadic neuroendocrine GEP tumors. The frequency of these mutations was 10% in our series, which may differ from that in other studies, due to the small number of cases analyzed.