Metformin Decreases Serum Thyroglobulin Concentration in Nonmedullary Thyroid Carcinoma.

Context: The conventional treatment of nonmedullary thyroid carcinoma (NMTC) includes surgical resection, thyrotropin (TSH) suppression, and 131-iodine. Some patients develop persistent/recurrent metastatic disease requiring expensive alternative therapies, such as external radiation and multikinase inhibitors, which may have clinically significant side effects. Recent in vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional trials analyzing the effect of metformin have been performed in humans. Objective: We hypothesize that metformin administration will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC burden. Methods: This retrospective institutional review board-approved study included 10 patients with persistent/recurrent NMTC who had exhausted conventional therapies including total thyroidectomy and 131-iodine. Five had detectable disease on computed tomography imaging. All had biochemical evidence of NMTC with Tg > 2.0 ng/mL with nondetectable serum thyroglobulin antibody concentrations. Five elected to have metformin treatment at doses varying from 500 to 2000 mg/day for 2 to 5 months. The remaining 5 served as untreated controls. Statistical significance was determined by the Mann-Whitney test. Results: Tg decreased (mean decrease = 21.7 ± 8.4%) in all 5 patients receiving metformin and increased (mean increase = 16.6 ± 12.1%) in all 5 controls (P < .01). TSH did not change significantly in either group. Conclusion: In summary, metformin caused a TSH-independent Tg decrease in patients with persistent/recurrent NMTC. More extensive studies are required to determine if metformin slows NMTC progression.

Familial nonmedullary thyroid carcinoma.

BACKGROUND: Nonmedullary thyroid carcinomas (NMTCs) originate from the thyroid epithelial cells and, until recently, were thought to arise sporadically without an inherited genetic predisposition. However, evidence of a familial predisposition to NMTC is accumulating. METHODS: This review addresses the strengths, weaknesses, and clinical implications of the observations indicating an inherited genetic predisposition to NMTC. These observations include epidemiologic studies, descriptions of large kindreds, and genetic analyses. RESULTS: Familial NMTC (FNMTC) may be caused by an inherited genetic predisposition and can be divided into two groups. The first group has an increased prevalence of NMTC within a familial cancer syndrome with a preponderance of nonthyroidal tumors. In the second group the predominant neoplasm is NMTC, although other neoplasms may occur with increased frequency. These disorders are the focus of this review. CONCLUSIONS: A family history in NMTC patients should be directed at detecting those familial tumor syndromes with a preponderance of NMTC as well as those familial tumor syndromes enriched in NMTC but with a preponderance of nonthyroidal tumors. Since the recurrence rates may be greater in FNMTC than in sporadic NMTC, careful monitoring is indicated for affected individuals. The advantages and disadvantages of screening asymptomatic members of FNMTC kindreds with thyroid ultrasound are discussed, and the final decision is deferred to the treating physicians and their patients. It is hoped that positional cloning research will identify the FNMTC susceptibility genes.

Glucocorticoid resistance and hypersensitivity.

This article emphasizes the disorders caused by mutations and polymorphisms of the alpha form of the glucocorticoid receptor. These disorders usually present with increased circulating cortisol concentrations and must be distinguished from Cushing's syndrome, because the therapies are markedly different. The other disorders present with clinical features limited to a specific organ system. Although they illustrate important physiologic and pathophysiologic principles, they usually are not confused with Cushing's syndrome.

Familial papillary thyroid carcinoma.

Over the last decade, several lines of evidence have been accumulated that support the existence of fPTC susceptibility genes. Preliminary clinical characteristics of fPTC have been identified, and linkage studies have identified the chromosomal locations of putative fPTC susceptibility genes. A logical clinical approach to fPTC is emerging.

Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity.

A naturally occurring ACTH receptor [melanocortin 2 receptor (MC2R)] mutation (F278C) has been identified in a subject with ACTH-independent Cushing's syndrome. Functional characterization of this mutant receptor reveals that it is associated with elevated basal cAMP accumulation when compared with wild-type receptor-expressing cell lines. Dose responsiveness is similar between wild-type and mutant receptors in cell lines expressing similar numbers of binding sites. In view of the location of this mutation in the C-terminal tail of the MC2R, desensitization and internalization were investigated and found to be impaired. Inhibition of protein kinase A by H89 blocks wild-type MC2R desensitization and also results in increased basal activity, as does alanine substitution of Ser 280 in the C-terminal tail. Alanine substitution of Ser 208, the consensus protein kinase A phosphorylation target in the third cytoplasmic loop also results in a reduction in desensitization without significant change in basal activity or internalization. These findings suggest a novel mechanism is involved in the apparently constitutive activation of the MC2R in which failure of desensitization appears to be associated with enhanced basal receptor activity.