Calcium, phosphorus and vitamin D disorders in uremia.

BACKGROUND: Alterations in calcium, phosphate (P) and vitamin D metabolism play a critical role in the development of secondary hyperparathyroidism (SH), parathyroid hyperplasia and soft tissue and vascular calcification. METHODOLOGY: Studies were performed in uremic dogs and rats fed a low and high P diet over a period of 1-4 months. In addition, in vitro studies were performed in normal parathyroid glands incubated in culture media containing 0.2 mM P (low) or 2.0 mM P (high). RESULTS: Uremic rats maintained on a low P diet did not develop SH or parathyroid hyperplasia. There was an enhancement of p21, the suppressor of the cell cycle, in these parathyroid glands. Opposite results were obtained using a high P diet. There was an enhancement of transforming growth factor-alpha and epidermal growth factor receptor, known enhancers of cell proliferation. In vitro studies demonstrated the direct effect of P on parathyroid hormone secretion. CONCLUSIONS: Early dietary P restriction prevents the development of SH and parathyroid hyperplasia. If dietary P restriction is applied to rats with established SH, there is a significant amelioration of SH and parathyroid hyperplasia. In addition, control of serum P in uremic patients is crucial in the prevention of vascular calcification.

Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism.

UNLABELLED: Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism. BACKGROUND: Secondary hyperparathyroidism (secondary HPT) in chronic renal insufficiency (CRI) is characterized by multiglandular hyperplasia. METHODS: In this study, we investigated the effects of the calcimimetic NPS R-568 on the parathyroid gland in rats with CRI induced by ligation of the renal arteries and severe secondary HPT induced by dietary phosphorus loading. Six days after surgery, high-phosphorus diet feeding was started, and NPS R-568 was administered to the rats for 56 days either by daily gavage (30 or 100 micromol/kg) or by continuous subcutaneous infusion (20 micromol/kg. day). RESULTS: After 54 days, serum PTH levels in vehicle-treated CRI rats were 1019 vs. 104 pg/mL in sham-operated controls. Infusion of NPS R-568 maintained serum PTH at levels comparable with those of sham-operated controls, whereas daily gavage also prevented much of the increase in CRI controls and decreased PTH levels intermittently in a dose-dependent fashion. Parathyroid gland enlargement was caused predominantly by hyperplasia. Total cell number per kg body wt was 3.5-fold higher in vehicle-treated CRI rats than in sham-operated controls. Both infusion and high-dose gavage of NPS R-568 completely prevented the increase in parathyroid cell number. CONCLUSION: These results demonstrate that the calcimimetic compound NPS R-568 can prevent both the increase in serum PTH levels and parathyroid hyperplasia in rats with CRI and severe secondary HPT. Moreover, these changes occurred despite decreases in serum 1, 25(OH)2D3 and increases in serum phosphate, suggesting a dominant role for the calcium receptor in regulating parathyroid cell proliferation.

Disorders of endocrine function following cancer therapies.

There is a growing body of literature detailing the endocrine consequences of cancer therapy. Certain conclusions can be drawn from the data presented. Patients who have received incidental hypothalamic--pituitary gland irradiation need to be followed carefully with serial dynamic hormonal evaluations, as they are at high risk of developing growth hormone and prolactin abnormalities and can develop other pituitary tropic hormone deficiencies as well. Children especially should be monitored closely as GH deficiency can be corrected if detected early. Patients who have received radiation to the head and neck region will need long-term (up to 30 years) surveillance for the development of thyroid cancer, hyperparathyroidism or hypothyroidism. Persistent elevations of TSH after incidental thyroidal irradiation are frequently seen and should be reversed with thyroid hormone administration in an attempt to minimize TSH stimulation of the irradiated gland. Radiation to the gonads will cause graded damage dependent on the dose delivered and the mode of fractionation. Age in a woman seems to be a significant factor of radiation sensitivity. Certain chemotherapeutic agents are radiomimetic in their gonadal effects; to date the alkylating agents have been most commonly implicated. FSH elevations herald gonadal damage (aspermia or loss of follicles) and should be looked for in patients receiving abdominal radiation or systemic chemotherapy. Leydig cell dysfunction occurs less frequently. Of all the iatrogenic endocrine complications discussed, some are eminently treatable, and some are quite preventable. Greater awareness of the unexpectedly high incidence of hormonal dysfunction can help lessen therapy-induced morbidity in long-term cancer survivors.