Syndromes of hormone excess can be caused by neoplastic growth of endocrine cells, autoimmune disorders, and excess hormone administration. Benign endocrine tumors, including parathyroid, pituitary, and adrenal adenomas, often retain the capacity to produce hormones, reflecting the fact that these tumors are relatively well differentiated. Many endocrine tumors exhibit subtle defects in their “set points” for feedback regulation. For example, in Cushing’s disease, impaired feed back inhibition of adrenocorticotropic hormone (ACTH) secretion is associated with autonomous function. However, the tumor cells are less sensitive to feedback inhibition, as evidenced by ACTH suppression at higher doses of dexamethasone (e.g., high-dose dexamethasone test). Similar set point defects are also typical of parathyroid adenomas and autonomously functioning thyroid nodules.
The molecular basis of some endocrine tumors, such as the multiple endocrine neoplasia (MEN) syndromes (MEN1, 2A, 2B), has provided important insights into tumorigenesis. MEN1 is characterized primarily by the triad of parathyroid, pancreatic islet, and pituitary tumors. MEN2 predisposes to medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. The MEN1 gene, located on chromosome 11q13, encodes a tumor-suppressor gene, menin. Analogous to the paradigm first described for retinoblastoma, the affected individual inherits a mutant copy of the MEN1 gene, and tumorigenesis ensues after a somatic “second hit” leads to loss of function of the normal MEN1 gene (through deletion or point mutations).
In contrast to inactivation of a tumor-suppressor gene, as occurs in MEN1 and most other inherited cancer syndromes, MEN2 is caused by activating mutations in a single allele. In this case, activating mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, lead to thyroid C-cell hyperplasia in childhood before the development of medullary thyroid carcinoma. Elucidation of this pathogenic mechanism has allowed early genetic screening for RET mutations in individuals at risk for MEN2, permitting identification of those who may benefit from prophylactic thyroidectomy and biochemical screening for pheochromocytoma and hyperparathyroidism.
Mutations that activate hormone receptor signaling have been identified in several GPCRs. For example, activating mutations of the luteinizing hormone (LH) receptor cause a dominantly transmitted form of male-limited precocious puberty, reflecting premature stimulation of testosterone synthesis in Leydig cells (Chap. 403). Activating mutations in these GPCRs are located predominantly in the trans membrane domains and induce receptor coupling to Gs α even in the absence of hormone. Consequently, adenylate cyclase is activated, and cyclic adenosine monophosphate (AMP) levels increase in a manner that mimics hormone action. A similar phenomenon results from activating mutations in Gs α. When these mutations occur early in development, they cause McCune-Albright syndrome. When they occur only in somatotropes, the activating Gs α mutations cause GH-secreting tumors and acromegaly.
In autoimmune Graves’ disease, antibody interactions with the thyroid-stimulating hormone (TSH) receptor mimic TSH action, leading to hormone overproduction. Analogous to the effects of activating mutations of the TSH receptor, these stimulating auto antibodies induce conformational changes in the TSH receptor that release it from a constrained state, thereby triggering receptor coupling to G proteins, and signaling induces excess thyroid hormone synthesis and secretion.
