Frontiers of Hormone Research最新文献

Primary hyperparathyroidism is among the most common causes of hypercalcemia. However, ingestion of medication, including hydrochlorathiazide, lithium, and foscarnet, excessive vitamin A ingestion, endocrinopathies such as hyperthyroidism, adrenal insufficiency, and acromegaly, abnormal nutrient intake such as parenteral nutrition in preterm infants and milk-alkali syndrome, and prolonged immobilization have all been associated with hypercalcemia. The most common cause of nonparathyroid hypercalcemia is neoplasia. Hypercalcemia is generally due to the secretion of parathyroid hormone (PTH)-related peptide (PTHrP) by a wide variety of nonmetastatic solid tumors, including squamous cell tumors but also hematologic tumors. PTHrP, although encoded by a distinct gene, shares amino acid sequence homology with PTH in the amino-terminal domain, which allows it to cross-react at a common G protein receptor, the type 1 PTH/PTHrP receptor (PTHR1), resulting in similar skeletal effects and effects on calcium and phosphorus metabolism. Increased PTHrP action with hypercalcemia may be seen in the benign disease Jansen's metaphyseal chondrodysplasia due to a gain-of-function mutation in PTHR1. Another humoral factor, 1,25-dihyroxyvitamin D [1,25(OH)2D] may be produced by lymphomas, but also by benign granulomatous disorders and may also cause hypercalcemia when its metabolism is genetically impaired. Vitamin D intoxication may cause hypercalcemia due to overproduction of the metabolite, 25 hydroxyvitamin D, apparently in the absence of conversion to 1,25(OH)2D. Malignancies metastatic to bone or arising in bone (such as multiple myeloma) may produce a variety of growth factors and cytokines, in addition to PTHrP, which can contribute to tumor growth as well as osteolysis and hypercalcemia.

Parathyroid hormone (PTH) disorders are characterized by a wide spectrum of clinical and biochemical presentations. The increasing use of serum PTH assay in the set of the diagnostic workout in patients with osteoporosis has identified patients with features of surgically confirmed primary hyperparathyroidism (PHPT) associated with persistent normal serum calcium levels, which has been recognized as a distinct entity from hypercalcemic PHPT (HPHPT) by the last international consensus. Normocalcemic PHPT (NPHPT) affects about 6-8% of PHPT patients. Although hypercalcemia is absent, patients with NPHPT experience kidney, bone, and cardiovascular impairments similar to those observed in HPHPT, suggesting that NPHPT may significantly affect the health of patients. Diagnosis of NPHPT requires an intensive diagnostic workup aimed to: (1) exclude all causes of secondary hyperparathyroidism, and (2) evaluate the occurrence of PTH-related diseases. The management of NPHPT is controversial in part due to lack of solid data about the natural history as well as the effects of surgical or medical treatments. Nonetheless, a clinical and biochemical follow-up is recommended in order to detect potential progression. When hypercalcemia and/or PTH-related disorders arise, parathyroidectomy can be considered. When surgery is not advisable, medical treatment aimed to increase bone mineral density may be a therapeutic option.

Several studies have investigated replacement therapy with recombinant human parathyroid hormone [rhPTH(1-84)] for patients affected by chronic hypoparathyroidism who are not adequately controlled with standard treatment. In 2015, the Food and Drug Administration (FDA) in the USA approved rhPTH(1-84), named Natpara®, for the pharmacological management of hypoparathyroidism. In Europe, in February 2017, the European Medicines Agency (EMA) recommended granting a conditional marketing authorization in the European Union for rhPTH(1-84). Here we review the studies conducted with rhPTH(1-84) and PTH(1-34) in patients with chronic hypoparathyroidism. The research done in this field has shown that replacement treatment with rhPTH(1-84) is an important therapeutic option for subjects with chronic hypoparathyroidism who are not well controlled with conventional treatment. However, further long-term investigations are needed.

Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are genetically determined variants of primary hyperparathyroidism. FHH usually has a benign course, and patients do not require treatment, whereas NSHPT is a severe disorder often requiring early parathyroidectomy for young patients to survive. Recent discoveries in the genetic basis and new findings in therapeutic approaches have led to a great interest in these rare diseases.

In the evolutionary process, the successful adaptation of living organisms initially to an aqueous and thereafter to an arid terrestrial environment posed radically different challenges to the maintenance of water balance. Whereas the former required defense against water excess, the latter called for water conservation. To meet such challenges, the mammalian nephron evolved mechanisms for increasing both water excretion by diluting and water conservation by concentrating the urine. This chapter reviews the process whereby the osmosensors control thirst and the secretion of the antidiuretic hormone (vasopressin) to allow for either urinary dilution or concentration and thereby delicately maintain tonicity of body fluids within a very narrow range. Central to this process is the now well-defined cellular pathway whereby vasopressin renders the collecting duct, water permeable. Disorders of vasopressin secretion and action result in disturbances of body fluids tonicity, which are clinically recognized as abnormalities in reduced plasma sodium concentration or hyponatremia.