Plasma levels of parathyroid hormone-related peptide are elevated in hyperprolactinemia and correlated to bone density status
Tóm tắt
Osteopenia is an important clinical manifestation of hyperprolactinemia. Bone loss in these patients has mainly been attributed to concomitant deficiency of gonadal hormones rather than to hyperprolactinemia per se. Parathyroid hormone-related peptide (PTHrP) is expressed in human mammary tissue, and elevated circulating PTHrP levels as well as concomitant hypercalcemia have been described during lactation. We sought to determine circulating PTHrP levels in patients with long-standing hyperprolactinemia and whether PTHrP may exert possible systemic effects on bone and mineral metabolism. We studied 45 patients (30 women and 15 men) with persisting hyperprolactinemia 6 ± 4 years (mean ± SD) after trans-sphenoidal surgery for prolactin-producing pituitary adenomas. PTHrP levels in 117 healthy controls were 10.6 ± 73 pmol-eq/l (mean ± SD). In hyperprolactinemic patients, plasma PTHrP was elevated to 303 ± 13.4 pmol-eq/l (p < 0.001, n = 45), and in patients with humoral hypercalcemia of malignancy PTHrP levels were 52.9 ± 29.6 (p < 0.001 to controls and hyperprolactinemic patients). Fifty-three percent of hyperprolactinemic patients (n = 24) had clearly elevated PTHrP levels (>2 SD). Retrospective immunocytochemical studies of the removed pituitary adenomas from 19 patients generally showed a higher degree of immunoreactivity for PTHrP (1–34) in all but one case when compared with normal pituitary tissue. Patients with elevated circulating PTHrP levels showed in most instances strong immunoreactivity to PTHrP in 70–100% of tumor cells. PTHrP was significantly correlated to blood pressure (systolic: r = –0.42, p < 0.005; diastolic: r = –0.41, p < 0.01), serum calcium (r = 0.40, p < 0.01), parathyroid hormone (r = –0.43, p < 0.005), and bone density measurements (r = –0.41, p < 0.005). Patients taking low doses of bromocriptine (n = 15) had similar reductions in bone mineral density despite lower prolactin levels (p < 0.005), and there was no correlation between either prolactin levels or estrogen status and bone mineral density measurements (r = –0.12 and r = –0.28, respectively). Our data demonstrate that circulating PTHrP levels are clearly elevated in approximately 50% of patients with pituitary hyperprolactinemia and suggests the pituitary adenomas to be the major source of PTHrP production. Independent of gonadal function and the degree of hyperprolactinemia, PTHrP functions as an active hormone and contributes substantially to bone loss seen in these patients.
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Tài liệu tham khảo
Nabarro, 1982, Pituitary prolactinomas., Clin Endocrinol, 17, 129, 10.1111/j.1365-2265.1982.tb01573.x
Klibanski, 1980, Decreased bone density in hyperprolactinemic women., N Engl J Med, 303, 1511, 10.1056/NEJM198012253032605
Klibanski, 1988, Effects of prolactin and estrogen deficiency in amenorrheic bone loss., J Clin Endocrinol Metab, 67, 124, 10.1210/jcem-67-1-124
Schlechte, 1987, Forearm and vertebral bone mineral in treated and untreated hyperprolactinemic amenorrhea., J Clin Endocrinol Metab, 64, 1021, 10.1210/jcem-64-5-1021
Klibanski, 1986, Increase in bone mass after treatment of hyperprolactinemic amenorrhea., N Engl J Med, 315, 542, 10.1056/NEJM198608283150903
Greenspan, 1986, Osteoporosis in men with hyperprolactinemic hypogonadism., Ann Intern Med, 104, 777, 10.7326/0003-4819-104-6-777
Ciccarelli, 1988, Vertebral bone density in non-amenorrheic hyperprolactinemic women., Clin Endocrinol, 28, 1, 10.1111/j.1365-2265.1988.tb01195.x
Koppelman, 1984, Vertebral body bone mineral content in hyperprolactinemic women., J Clin Endocrinol Metab, 59, 1050, 10.1210/jcem-59-6-1050
Nyström, 1988, Bone mineral content in normally menstruating women with hyperprolactinemia., Hormone Res, 29, 214, 10.1159/000181006
Caraceni, 1985, Increased forearm bone mineral content after bromocriptine treatment in hyperprolactinemia., Calcif Tissue Int, 37, 687, 10.1007/BF02554932
Schlechte, 1983, Bone density in amenorrheic women with and without hyperprolactinemia., J Clin Endocrinol Metab, 56, 1120, 10.1210/jcem-56-6-1120
Jacobs, 1976, Clinical and endocrine features of hyperprolactinemic amenorrhoea., Clin Endocrinol, 5, 439, 10.1111/j.1365-2265.1976.tb01974.x
Suva, 1987, A parathyroid hormone-related protein implicated in malignant hypercalcemia: Cloning and expression., Science, 237, 893, 10.1126/science.3616618
Henderson, 1990, Circulating concentrations of parathyroidlike peptide in malignancy and in hyperparathyroidism., J Bone Miner Res, 5, 105, 10.1002/jbmr.5650050203
Weir, 1988, Isolation of 16,000-dalton parathyroid hormone-like proteins from two animal tumors causing humoral hypercalcemia of malignancy., Endocrinology, 123, 2744, 10.1210/endo-123-6-2744
Ikeda, 1988, Identification of transcripts encoding a parathyroid hormone-like peptide in messenger RNAs from a variety of human and animal tumors associated with humoral hypercalcemia of malignancy., J Clin Invest, 81, 2010, 10.1172/JCI113551
Burtis, 1990, Immunochemical characterization of circulating parathyroid hormone-related protein in patients with humoral hypercalcemia of malignancy., N Engl J Med, 322, 1106, 10.1056/NEJM199004193221603
Thiede, 1988, Expression of a calcium-mobilizing parathyroid hormone-like peptide in lactating mammary tissue., Science, 242, 278, 10.1126/science.3175653
Ikeda, 1988, Expression of messenger ribonucleic acids encoding a parathyroid hormone-like peptide in normal human and animal tissues with abnormal expression in human parathyroid adenomas., Mol Endocrinol, 2, 1230, 10.1210/mend-2-12-1230
Thiede, 1989, The mRNA encoding a parathyroid hormone-like peptide is produced in mammary tissue in response to elevations in serum prolactin., Mol Endocrinol, 3, 1443, 10.1210/mend-3-9-1443
Khosla, 1991, Parathyroid hormone-related protein and hypercalcemia secondary to massive mammary hyperplasia., N Engl J Med, 322, 1157
Hoekman, 1990, Modulation of the production of a parathyroid hormone-like protein in human squamous carcinoma cell lines by interaction with fibroblasts., Cancer Res, 50, 3589
Scharla, 1991, PTH-related protein (PTHrP) im Serum von Patienten mit Tumorhyperkalzämie., Med Klinik, 86, 186
Simpson, 1983, Absence of parathyroid hormone messenger RNA in nonparathyroid tumors associated with hypercalcemia., N Engl J Med, 309, 325, 10.1056/NEJM198308113090601
Shan, 1994, Cardiovascular effects of human parathyroid hormone and parathyroid hormone-related peptide., J Cardiovasc Pharmacol, 23, S38
Nickols, 1989, Hypotension and cardiac stimulation due to the parathyroid hormone-related protein, humoral hypercalcemia of malignancy factor., Endocrinology, 125, 824, 10.1210/endo-125-2-834
Stewart, 1982, Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity., J Clin Endocrinol Metab, 55, 219, 10.1210/jcem-55-2-219
Wada, 1992, Parathyroid hormone-related protein as a cause of hypercalcemia in a B-cell type malignant lymphoma., Internal Med, 31, 968, 10.2169/internalmedicine.31.968
De la Piedra, 1987, Osteocalcin and urinary hydroxyproline/creatinine ratio in the differential diagnosis of primary hyperparathyroidism and hypercalcemia of malignancy., Scand J Clin Lab Invest, 47, 587, 10.3109/00365518709168473
Kukreja, 1990, Tumor resection and antibodies to parathyroid hormone-related protein cause similar changes on bone histomorphometry in hypercalcemia of cancer., Endocrinology, 127, 305, 10.1210/endo-127-1-305
Rosol, 1988, Effects of infusion of human parathyroid hormone-related protein (1–40) in nude mice: histomorphometric and biochemical investigations., J Bone Miner Res, 3, 699, 10.1002/jbmr.5650030616
Kukreja, 1989, Comparison of the effects of parathyroid hormone-related protein (PTHrP) (1–34) and PTHrP (1–141) on quantitative bone histomorphometry in mice., J Bone Miner Res, 4, S319
Mundy, 1985, Tumor products and the hypercalcemia of malignancy., J Clin Invest, 76, 391, 10.1172/JCI111984
Orloff, 1994, Parathyroid hormone-related protein as a prohormone: posttranslational processing and receptor interactions., Endocrinol Rev, 15, 40
Fiore, 1988, Bone mineral content of the hyperprolactinemic rat femur by single photon absorptiometry., Hormone Metabol Res, 20, 40, 10.1055/s-2007-1010744
Whittaker, 1984, Maintained fertility in a patient with hyperprolactinemia due to big, big prolactin., J Clin Endocrinol Metab, 53, 863, 10.1210/jcem-53-4-863
Jackson, 1989, Persistence of large molecular weight prolactin secretion during pregnancy in women with macroprolactinemia and its presence in fetal cord blood., J Clin Endocrin Metabol, 68, 1046, 10.1210/jcem-68-6-1046
Orimo, 1972, Increased sensitivity of bone to parathyroid hormone in ovariectomized rats., Endocrinology, 90, 760, 10.1210/endo-90-3-760
Greenspan, 1989, Importance of gonadal steroids to bone mass in men with hyperprolactinemic hypogonadism., Ann Intern Med, 110, 526, 10.7326/0003-4819-110-7-526
Riggs, 1992, The prevention and treatment of osteoporosis., N Engl J Med, 327, 620, 10.1056/NEJM199208273270908
Grill, 1992, Parathyroid hormone-related protein: a possible endocrine function in lactation., Clin Endocrinol, 37, 405, 10.1111/j.1365-2265.1992.tb02350.x
Asa, 1990, Parathyroid hormone-like peptide in normal and neoplastic human endocrine disease., J Clin Endocrinol Metabol, 71, 1112, 10.1210/jcem-71-5-1112
Ito, 1993, Expression of parathyroid hormone related peptide in human pituitary tumours., J Clin Pathol, 48, 682, 10.1136/jcp.46.7.682
Pang, 1988, Parathyroid hormone-like activity in brains of tetrapod vertebrates., Am J Physiol, 255, R635
Pang, 1988, Immunocytochemical distribution of PTH immunoreactivity in vertebrate brains., Am J Physiol, 255, R643
Holt, 1994, Regulation of parathyroid hormone-related peptide gene expression by estrogen in GH4Cl rat pituitary cells has the pattern of a primary response gene., J Neurochem, 62, 1239, 10.1046/j.1471-4159.1994.62041239.x